BioPAX pathway converted from "Diseases of Cellular Senescence" in the Reactome database. Diseases of Cellular Senescence Cellular senescence plays an important role in normal aging, as well as in age-related diseases. Impaired cellular senescence contributes to malignant transformation and cancer development. Presence of an excessive number of senescent cells that are not cleared by the immune system, however, promotes tissue inflammation and creates a microenvironment suitable for growth of neighboring malignant cells. Besides cancer, senescence is also involved in atherosclerosis, osteoarthritis and diabetes (Childs et al. 2015, He and Sharpless 2017). Authored: Orlic-Milacic, Marija, 2018-12-24 Reviewed: Bennett, Dorothy C, 2019-04-23 Reviewed: Nathan, Vaishnavi, 2019-06-03 Reviewed: Hayward, Nicholas K, 2019-06-03 Edited: Orlic-Milacic, Marija, 2019-05-07 Evasion of Oncogene Induced Senescence Due to p16INK4A Defects CDKN2A基因由四个外显子,外显子1β, exon 1alpha, exon 2 and exon 3, going from the proximal to the distal gene end. There are two promoters in the CDKN2A gene locus. The promoter located between exons 1beta and 1alpha regulates transcription of the p16INK4A mRNA, which consists of exon 1alpha, exon 2 and exon 3 (only partially translated), and encodes a cyclin-dependent kinase inhibitor p16INK4A (also known as CDKN2A isoform 1, p16, INK4A, CDKN2A, CDK4I or MTS-1). The promoter located upstream of exon 1beta regulates transcription of the p14-ARF mRNA, which consists of exon 1beta, exon 2 (partially translated) and exon 3 (untranslated). The p14ARF mRNA is translated in a different reading frame from the p16INK4A mRNA and produces the tumor suppressor ARF (also known as p14ARF or CDKN2A isoform 4), an inhibitor of MDM2 E3 ubiquitin ligase-mediated degradation of TP53 (p53).
Wild type p16INK4A is able to form a complex with either CDK4 or CDK6 and prevent formation of catalytically active CDK complexes consisting of CDK4 or CDK6 and D-type cyclins (CCND). Thus, p16INK4A prevents hyperphosphorylation of RB-family proteins, required for initiation of DNA replication in RB1-competent cells. Expression of p16INK4A increases in response to strong oncogenic signaling, leading to accelerated cellular senescence (programmed cell cycle arrest). Expression of p16INK4A also increases after excessive proliferation, including that following oncogene activation by mutation in vivo. Loss-of-function of p16INK4A frequently occurs in cancer, usually through loss of p16INK4A protein expression due to promoter hypermethylation or CDKN2A gene deletion (Merlo et al. 1995, Herman et al. 1995, Gonzalez-Zulueta et al. 1995, Wong et al. 1997, Witkiewicz et al. 2011, Shima et al. 2011, Tamayo-Orrego et al. 2016). Missense, nonsense and frameshift mutations in the CDKN2A locus can also impair p16INK4A function through expression of non-functional substitution mutants or truncated proteins (Kamb et al. 1994, Bartsch et al. 1995, Castellano et al. 1997). Germline intronic CDKN2A mutations that create aberrant splicing sites and result in expression of non-functional splicing variants of p16INK4A have been reported in familial melanoma (Harland et al. 2001, Harland et al. 2005). A CDKN2A gene mutation in the region encoding the 5'UTR of p16INK4A, reported in familial melanoma, creates a novel translation start codon and diminishes translation from the wild type start codon (Liu et al. 1999). However, mutations in the non-coding regions of the CDKN2A gene are rare (Pollock et al. 2001).
Based on cell culture studies, p16INK4A defects enable precancerous and cancerous cells to delay or evade senescence under oncogenic signaling stress (Ruas et al. 1999, Haferkamp et al. 2008, Rayess et al. 2012, Jeanblanc et al. 2012, LaPak and Burd 2014, Sharpless and Sherr 2015). Establishment of an in vivo role of oncogene induced senescence, and thus an in vivo role of p16INK4A in this context, have been difficult owing to lack of specific biomarkers and interconnectedness of various senescence triggers (Baek and Ryeom 2017, reviewed in Sharpless and Sherr 2015).
Genomic deletions in the CDKN2A locus affect p14ARF, unless they are limited to exon 1alpha. The p14ARF promoter can also be hypermethylated in cancer, leading to loss of p14ARF expression. Some missense mutations occurring in exon 2 of the CDKN2A gene affect the p14ARF protein sequence. However, p14ARF mutants usually appear to be less functionally compromised than their p16INK4A counterparts. Most functional tests on p14ARF mutants examine the effect of mutations on MDM2 binding and TP53-mediated transcription of CDKN1A (p21), as well as sub-nuclear localization of p14ARF (Zhang and Xiong 1999, Schmitt et al. 1999, Eischen et al. 1999, Pinyol et al. 2000, Bostrom et al. 2001, Laud et al. 2006). Still, there are poorly explored functions of p14ARF that may be significantly affected in mutant p14ARF proteins detected in cancer (Itahana and Zhang 2008, Dominguez-Brauer et al. 2010). Authored: Orlic-Milacic, Marija, 2018-12-24 Reviewed: Bennett, Dorothy C, 2019-04-23 Reviewed: Nathan, Vaishnavi, 2019-06-03 Reviewed: Hayward, Nicholas K, 2019-06-03 Edited: Orlic-Milacic, Marija, 2019-05-07 Evasion of Oncogene Induced Senescence Due to Defective p16INK4A binding to CDK4 and CDK6 Missense and nonsense mutations in the CDKN2A gene that result in amino acid substitutions in p16INK4A or p16INK4A truncations, impairing its ability to bind to CDK4 and CDK6, interfere with p16INK4A-mediated induction of cellular senescence in response to oncogenic signaling (Haferkamp et al. 2008).
Loss-of-function mutations in p16INK4A can also contribute to cancer by interfering with p16INK4A-mediated inhibition of NFKB signaling (Becker et al. 2005). Authored: Orlic-Milacic, Marija, 2018-12-24 Reviewed: Bennett, Dorothy C, 2019-04-23 Reviewed: Nathan, Vaishnavi, 2019-06-03 Reviewed: Hayward, Nicholas K, 2019-06-03 Edited: Orlic-Milacic, Marija, 2019-05-07 LEFT-TO-RIGHT p16INK4A分子突变体不绑定到CDK6 野生型p16INK4A分子能够形成一个复杂either CDK4 or CDK6 and prevent formation of catalytically active CDK complexes consisting of CDK4 or CDK6 and D-type cyclins (CCND). Several CDKN2A missense mutations found in cancer lead to amino acid substitutions in p16INK4A that impair binding of p16INK4A mutants to both CDK4 and CDK6. Missense mutations in p16INK4A are recessive and are usually found in combination with genomic deletion or epigenetic silencing of the other CDKN2A allele (Kamb et al. 1994, Castellano et al. 1997, Liew et al. 1999). Inactivating mutations in the coding sequence of p16INK4A can also be accompanied with loss of heterozygosity (LOH) (Castellano et al. 1997, Kumar et al. 1999 , Liew et al. 1999). Functionally tested p16INK4A mutants that are unable to bind to either CDK4 or CDK6 or show little residual binding, and are unable to inhibit cellular proliferation are:

p16INK4A A20P (Ruas et al. 1999, Jones et al. 2007)
p16INK4A M53I (Harland et al. 1997, Walker et al. 1999, Becker et al. 2001)
p16INK4A P81L (Walker et al. 1999)
p16INK4A P81T (Kannengiesser et al. 2009, McKenzie et al. 2010)
p16INK4A D84G (Yarbrough et al. 1999)
p16INK4A D84H (Ruas et al. 1999)
p16INK4A D84N (Ruas et al. 1999)
p16INK4A D84V (Yarbrough et al. 1999)
p16INK4A D84Y (Ruas et al. 1999)
p16INK4A R87P (Walker et al. 1999, Yarbrough et al. 1999)
p16INK4A G101W (Walker et al. 1999, Kannengiesser et al. 2009, McKenzie et al. 2010, Scaini et al. 2014)
p16INK4A P114L (Harland et al. 1997)
p16INK4A V126D (Walker et al. 1999, Becker et al. 2001)

Based on the affected amino acid residue, the following p16INK4A missense mutants that have not been tested for their ability to bind to CDK4 or CDK6, but have been reported in cancer and predicted to be pathogenic ( COSMIC database: Forbes et al. 2017) are annotated as candidates:

p16INK4A A20E
p16INK4A A20T
p16INK4A P81H
p16INK4A P81R
p16INK4A P81S
p16INK4A D84A
p16INK4A G101V
p16INK4A P114H
p16INK4A P114R
p16INK4A P114S
p16INK4A P114T
p16INK4A V126A
p16INK4A V126F
p16INK4A V126I

.p16INK4A P114S was shown to have a reduced binding to CDK4 (Kannengiesser et al. 2009) and a reduced ability to inhibit cellular proliferation (Scaini et al. 2014). p16INK4A A20S retains the ability to bind to CDK4 and CDK6 and to inhibit cellular proliferation (Yarbrough et al. 1999). p16INK4A R87W (Walker et al. 1999) and p16INK4A R87L (Yarbrough et al. 1999) retain the ability to bind to CDK4 and CDK6, but are unable to induce cell cycle arrest. Mutants p16INK4A A20S, p16INK4A R87W and p16INK4A R87L have not been annotated.
Some p16INK4A missense mutants are temperature sensitive, and their ability to bind to CDK4 and CDK6 can only be properly assessed at the physiological temperature of 37 degrees Celsius (Becker et al. 2001). Not controlling experimental temperature can be one source of inconsistencies when evaluating functionality of p16INK4A mutants, but many other variabilities in experimental systems and techniques can also influence the results of binding assays. A p16INK4A mutant with a preserved ability to bind to CDK4 and CDK6 may still not be able to inhibit their cyclin-dependent activation. However, the loss of CDK inhibitory function in p16INK4A mutants that do bind to CDK4 and CDK6 has not been tested directly.
Nonsense mutations in the second exon of the CDKN2A gene that lead to premature termination of p16INK4A mRNA translation are frequent in cancer. While the mRNAs of predicted p16INK4A truncation mutants can be detected, the truncated proteins cannot:

p16INK4A R58* (Castellano et al. 1997)
p16INK4A R80* (Fahham et al. 2010)
p16INK4A E88* (Castellano et al. 1997)
p16INK4A W110* (Castellano et al. 1997)

In addition, it was shown that the C-terminal half of p16INK4A is critical for binding to CDK4 and CDK6, and inhibition of cellular proliferation (Fahham et al. 2010).
The following nonsense and frameshift truncation mutants have not been functionally tested and are annotated as candidates:

p16INK4A E10*
p16INK4A S12*
p16INK4A W15*
p16INK4A E26*
p16INK4A E27*
p16INK4A E33*
p16INK4A Y44*
p16INK4A Q50*
p16INK4A E61*
p16INK4A E69*
p16INK4A C72*
p16INK4A P75*
p16INK4A E119*
p16INK4A E120*

The following recurrent frameshift truncations mutants that lack the C-terminal half of wild type p16INK4A and are therefore assumed to be unable to bind to CDK4 or CDK6 are also annotated as candidates:

p16INK4A S7fs*8
p16INK4A W15fs*1
p16INK4A L16fs*9
p16INK4A T18fs*15
p16INK4A T18fs*8
p16INK4A G23fs*3
p16INK4A A36fs*17
p16INK4A L37fs*16
p16INK4A N39fs*14
p16INK4A Y44fs*1

Authored: Orlic-Milacic, Marija, 2018-12-24 Reviewed: Bennett, Dorothy C, 2019-04-23 Reviewed: Nathan, Vaishnavi, 2019-06-03 Reviewed: Hayward, Nicholas K, 2019-06-03 Converted from EntitySet in Reactome p16INK4A LoF mutants (CDK4/6) Reactome DB_ID: 9630804 CDKN2A A20P p16INK4A A20P p16INK4A Ala20Pro CDKN2A Ala20Pro Reactome DB_ID: 9630805 cytosol GENE ONTOLOGY GO:0005829 UniProt:P42771 CDKN2A CDKN2A CDKN2 MTS1 FUNCTION Acts as a negative regulator of the proliferation of normal cells by interacting strongly with CDK4 and CDK6. This inhibits their ability to interact with cyclins D and to phosphorylate the retinoblastoma protein.SUBUNIT Heterodimer with CDK4 or CDK6. Predominant p16 complexes contained CDK6. Interacts with CDK4 (both 'T-172'-phosphorylated and non-phosphorylated forms); the interaction inhibits cyclin D-CDK4 kinase activity. Interacts with ISCO2.TISSUE SPECIFICITY Widely expressed but not detected in brain or skeletal muscle. Isoform 3 is pancreas-specific.PTM Phosphorylation seems to increase interaction with CDK4.DISEASE The association between cutaneous and uveal melanomas in some families suggests that mutations in CDKN2A may account for a proportion of uveal melanomas. However, CDKN2A mutations are rarely found in uveal melanoma patients.SIMILARITY Belongs to the CDKN2 cyclin-dependent kinase inhibitor family.CAUTION The proteins described here are encoded by the gene CDKN2A, but are completely unrelated in terms of sequence and function to tumor suppressor ARF (AC Q8N726) which is encoded by the same gene. Homo sapiens NCBI Taxonomy 9606 UniProt P42771 20 EQUAL L-alanine removal MOD MOD:01631 1 EQUAL 156 EQUAL Reactome Database ID Release 77 9630805 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9630805 Reactome R-HSA-9630805 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9630805.1 Reactome //www.joaskin.com COSMIC COSV58693206 additional information MI MI:0361 CDKN2A M53I p16INK4A M53I p16INK4A Met53Ile CDKN2A Met53Ile Reactome DB_ID: 9630911 53 EQUAL L-methionine removal MOD MOD:01643 1 EQUAL 156 EQUAL Reactome Database ID Release 77 9630911 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9630911 Reactome R-HSA-9630911 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9630911.1 COSMIC COSV58683319 CDKN2A P114L p16INK4A P114L CDKN2A Pro114Leu p16INK4A Pro114Leu Reactome DB_ID: 9630916 114 EQUAL L-proline removal MOD MOD:01645 1 EQUAL 156 EQUAL Reactome Database ID Release 77 9630916 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9630916 Reactome R-HSA-9630916 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9630916.1 COSMIC COSV58683051 COSMIC COSM53077 COSMIC COSV58685522 CDKN2A G101W p16INK4A G101W p16INK4A Gly101Trp CDKN2A Gly101Trp Reactome DB_ID: 9631257 101 EQUAL glycine removal MOD MOD:01638 1 EQUAL 156 EQUAL Reactome Database ID Release 77 9631257 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9631257 Reactome R-HSA-9631257 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9631257.1 COSMIC COSV58692144 COSMIC COSM36176 CDKN2A V126D p16INK4A V126D p16INK4A Val126Asp CDKN2A Val126Asp Reactome DB_ID: 9631055 126 EQUAL L-valine removal MOD MOD:01650 1 EQUAL 156 EQUAL Reactome Database ID Release 77 9631055 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9631055 Reactome R-HSA-9631055 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9631055.1 COSMIC COSV58684293 COSMIC COSM329718 CDKN2A P81L p16INK4A P81L CDKN2A Pro81Leu p16INK4A Pro81Leu Reactome DB_ID: 9632280 81 EQUAL 1 EQUAL 156 EQUAL Reactome Database ID Release 77 9632280 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9632280 Reactome R-HSA-9632280 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9632280.1 COSMIC COSV58683884 COSMIC COSV58718874 COSMIC COSM1735692 CDKN2A P81T p16INK4A P81T CDKN2A Pro81Thr p16INK4A Pro81Thr Reactome DB_ID: 9632275 81 EQUAL 1 EQUAL 156 EQUAL Reactome Database ID Release 77 9632275 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9632275 Reactome R-HSA-9632275 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9632275.1 COSMIC COSV58720289 CDKN2A R87P p16INK4A R87P p16INK4A Arg87Pro CDKN2A Arg87Pro Reactome DB_ID: 9632335 87 EQUAL L-arginine removal MOD MOD:01632 1 EQUAL 156 EQUAL Reactome Database ID Release 77 9632335 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9632335 Reactome R-HSA-9632335 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9632335.1 COSMIC COSV58683633 CDKN2A D84G p16INK4A D84G p16INK4A Asp84Gly CDKN2A Asp84Gly Reactome DB_ID: 9632461 84 EQUAL L-aspartic acid removal MOD MOD:01634 1 EQUAL 156 EQUAL Reactome Database ID Release 77 9632461 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9632461 Reactome R-HSA-9632461 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9632461.1 COSMIC COSV58688961 CDKN2A D84V p16INK4A D84V p16INK4A Asp84Val CDKN2A Asp84Val Reactome DB_ID: 9632465 84 EQUAL 1 EQUAL 156 EQUAL Reactome Database ID Release 77 9632465 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9632465 Reactome R-HSA-9632465 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9632465.1 COSMIC COSV58705912 CDKN2A D84H p16INK4A D84H p16INK4A Asp84His CDKN2A Asp84His Reactome DB_ID: 9632489 84 EQUAL 1 EQUAL 156 EQUAL Reactome Database ID Release 77 9632489 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9632489 Reactome R-HSA-9632489 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9632489.1 COSMIC COSV58694349 CDKN2A D84N p16INK4A D84N p16INK4A Asp84Asn CDKN2A Asp84Asn Reactome DB_ID: 9632483 84 EQUAL 1 EQUAL 156 EQUAL Reactome Database ID Release 77 9632483 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9632483 Reactome R-HSA-9632483 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9632483.1 CDKN2A D84Y p16INK4A D84Y p16INK4A Asp84Tyr CDKN2A Asp84Tyr Reactome DB_ID: 9632478 84 EQUAL 1 EQUAL 156 EQUAL Reactome Database ID Release 77 9632478 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9632478 Reactome R-HSA-9632478 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9632478.1 COSMIC COSV58683210 CDKN2A E88* p16INK4A E88* p16INK4A E88TER p16INK4A Glu88TER p16INK4A Glu88* CDKN2A E88TER CDKN2A Glu88TER CDKN2A Glu88* Reactome DB_ID: 9632588 88 EQUAL L-glutamic acid removal MOD MOD:01636 1 EQUAL 87 EQUAL Reactome Database ID Release 77 9632588 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9632588 Reactome R-HSA-9632588 2 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9632588.2 COSMIC COSM144161 COSMIC COSV58683071 CDKN2A R58* p16INK4A R58* p16INK4A R58TER p16INK4A Arg58TER p16INK4A Arg58* CDKN2A R58TER CDKN2A Arg58TER CDKN2A Arg58* Reactome DB_ID: 9632582 58 EQUAL 1 EQUAL 57 EQUAL Reactome Database ID Release 77 9632582 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9632582 Reactome R-HSA-9632582 2 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9632582.2 COSMIC COSV58683779 COSMIC COSM53073 COSMIC COSV58687698 COSMIC COSV58682666 CDKN2A R80* p16INK4A R80* p16INK4A R80TER p16INK4A Arg80TER p16INK4A Arg80* CDKN2A R80TER CDKN2A Arg80TER CDKN2A Arg80* Reactome DB_ID: 9632586 80 EQUAL 1 EQUAL 79 EQUAL Reactome Database ID Release 77 9632586 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9632586 Reactome R-HSA-9632586 2 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9632586.2 COSMIC COSM13679 COSMIC COSV58686001 CDKN2A W110* p16INK4A W110* p16INK4A W110TER p16INK4A Trp110TER p16INK4A Trp110* CDKN2A W110TER CDKN2A Trp110TER CDKN2A Trp110* Reactome DB_ID: 9632585 110 EQUAL L-tryptophan removal MOD 国防部:01648 1 EQUAL 109 EQUAL Reactome Database ID Release 77 9632585 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9632585 Reactome R-HSA-9632585 2 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9632585.2 COSMIC COSM13783 COSMIC COSV58682976 COSMIC COSV58682827 CDKN2A A20E p16INK4A A20E p16INK4A Ala20Glu CDKN2A Ala20Glu Reactome DB_ID: 9630855 20 EQUAL 1 EQUAL 156 EQUAL Reactome Database ID Release 77 9630855 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9630855 Reactome R-HSA-9630855 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9630855.1 CDKN2A A20T p16INK4A A20T p16INK4A Ala20Thr CDKN2A Ala20Thr Reactome DB_ID: 9630861 20 EQUAL 1 EQUAL 156 EQUAL Reactome Database ID Release 77 9630861 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9630861 Reactome R-HSA-9630861 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9630861.1 COSMIC COSV58729858 CDKN2A P114S p16INK4A P114S CDKN2A Pro114Ser p16INK4A Pro114Ser Reactome DB_ID: 9631027 114 EQUAL 1 EQUAL 156 EQUAL Reactome Database ID Release 77 9631027 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9631027 Reactome R-HSA-9631027 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9631027.1 COSMIC COSV58704478 CDKN2A P114T p16INK4A P114T CDKN2A Pro114Thr p16INK4A Pro114Thr Reactome DB_ID: 9631034 114 EQUAL 1 EQUAL 156 EQUAL Reactome Database ID Release 77 9631034 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9631034 Reactome R-HSA-9631034 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9631034.1 COSMIC COSV58704067 CDKN2A P114H p16INK4A P114H p16INK4A Pro114His CDKN2A Pro114His Reactome DB_ID: 9631043 114 EQUAL 1 EQUAL 156 EQUAL Reactome Database ID Release 77 9631043 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9631043 Reactome R-HSA-9631043 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9631043.1 COSMIC COSV58690307 CDKN2A P114R p16INK4A P114R p16INK4A Pro114Arg CDKN2A Pro114Arg Reactome DB_ID: 9631046 114 EQUAL 1 EQUAL 156 EQUAL Reactome Database ID Release 77 9631046 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9631046 Reactome R-HSA-9631046 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9631046.1 COSMIC COSV58692178 CDKN2A G101V p16INK4A G101V p16INK4A Gly101Val CDKN2A Gly101Val Reactome DB_ID: 9631263 101 EQUAL 1 EQUAL 156 EQUAL Reactome Database ID Release 77 9631263 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9631263 Reactome R-HSA-9631263 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9631263.1 CDKN2A V126A p16INK4A V126A p16INK4A Val126Ala CDKN2A Val126Ala Reactome DB_ID: 9631126 126 EQUAL 1 EQUAL 156 EQUAL Reactome Database ID Release 77 9631126 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9631126 Reactome R-HSA-9631126 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9631126.1 COSMIC COSV58705336 CDKN2A V126F p16INK4A V126F p16INK4A Val126Phe CDKN2A Val126Phe Reactome DB_ID: 9631120 126 EQUAL 1 EQUAL 156 EQUAL Reactome Database ID Release 77 9631120 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9631120 Reactome R-HSA-9631120 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9631120.1 COSMIC COSV58698939 CDKN2A V126I p16INK4A V126I p16INK4A Val126Ile CDKN2A Val126Ile Reactome DB_ID: 9631130 126 EQUAL 1 EQUAL 156 EQUAL Reactome Database ID Release 77 9631130 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9631130 Reactome R-HSA-9631130 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9631130.1 COSMIC COSV58727425 CDKN2A P81S p16INK4A P81S CDKN2A Pro81Ser p16INK4A Pro81Ser Reactome DB_ID: 9632287 81 EQUAL 1 EQUAL 156 EQUAL Reactome Database ID Release 77 9632287 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9632287 Reactome R-HSA-9632287 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9632287.1 COSMIC COSV58687028 CDKN2A P81R p16INK4A P81R CDKN2A Pro81Arg p16INK4A Pro81Arg Reactome DB_ID: 9632294 81 EQUAL 1 EQUAL 156 EQUAL Reactome Database ID Release 77 9632294 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9632294 Reactome R-HSA-9632294 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9632294.1 COSMIC COSV58717232 COSMIC COSM6022894 CDKN2A Pro81 p16INK4A P81H CDKN2A P81His p16INK4A Pro81His Reactome DB_ID: 9632293 81 EQUAL 1 EQUAL 156 EQUAL Reactome Database ID Release 77 9632293 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9632293 Reactome R-HSA-9632293 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9632293.1 COSMIC COSV58697231 CDKN2A D84A p16INK4A D84A p16INK4A Asp84Ala CDKN2A Asp84Ala Reactome DB_ID: 9632486 84 EQUAL 1 EQUAL 156 EQUAL Reactome Database ID Release 77 9632486 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9632486 Reactome R-HSA-9632486 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9632486.1 CDKN2A E120* p16INK4A E120* p16INK4A E120TER p16INK4A Glu120TER p16INK4A Glu120* CDKN2A E120TER CDKN2A Glu120TER CDKN2A Glu120* Reactome DB_ID: 9632587 120 EQUAL 1 EQUAL 119 EQUAL Reactome Database ID Release 77 9632587 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9632587 Reactome R-HSA-9632587 2 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9632587.2 COSMIC COSM14264 COSMIC COSV58683444 CDKN2A E10* p16INK4A E10* p16INK4A E10TER p16INK4A Glu10TER p16INK4A Glu10* CDKN2A E10TER CDKN2A Glu10TER CDKN2A Glu10* Reactome DB_ID: 9648382 10 EQUAL 1 EQUAL 9 EQUAL Reactome Database ID Release 77 9648382 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9648382 Reactome R-HSA-9648382 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9648382.1 COSMIC COSV58705987 CDKN2A S12* p16INK4A S12* p16INK4A S12TER p16INK4A Ser12TER p16INK4A Ser12* CDKN2A S12TER CDKN2A Ser12TER CDKN2A Ser12* Reactome DB_ID: 9648383 12 EQUAL L-serine removal MOD MOD:01646 1 EQUAL 11 EQUAL Reactome Database ID Release 77 9648383 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9648383 Reactome R-HSA-9648383 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9648383.1 COSMIC COSV58689693 COSMIC COSM4381091 CDKN2A C72* p16INK4A C72* p16INK4A C72TER p16INK4A Cys72TER p16INK4A Cys72* CDKN2A C72TER CDKN2A Cys72TER CDKN2A Cys72* Reactome DB_ID: 9648389 72 EQUAL L-cysteine removal MOD MOD:01635 1 EQUAL 71 EQUAL Reactome Database ID Release 77 9648389 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9648389 Reactome R-HSA-9648389 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9648389.1 COSMIC COSV58683179 COSMIC COSM6024047 CDKN2A E119* p16INK4A E119* p16INK4A E119TER p16INK4A Glu119TER p16INK4A Glu119* CDKN2A E119TER CDKN2A Glu119TER CDKN2A Glu119* Reactome DB_ID: 9648390 119 EQUAL 1 EQUAL 118 EQUAL Reactome Database ID Release 77 9648390 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9648390 Reactome R-HSA-9648390 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9648390.1 COSMIC COSV58688112 COSMIC COSV58695431 CDKN2A E26* p16INK4A E26* p16INK4A E26TER p16INK4A Glu26TER p16INK4A Glu26* CDKN2A E26TER CDKN2A Glu26TER CDKN2A Glu26* Reactome DB_ID: 9648392 26 EQUAL 1 EQUAL 25 EQUAL Reactome Database ID Release 77 9648392 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9648392 Reactome R-HSA-9648392 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9648392.1 COSMIC COSV58701530 CDKN2A E27* p16INK4A E27* p16INK4A E27TER p16INK4A Glu27TER p16INK4A Glu27* CDKN2A E27TER CDKN2A Glu27TER CDKN2A Glu27* Reactome DB_ID: 9648387 27 EQUAL 1 EQUAL 26 EQUAL Reactome Database ID Release 77 9648387 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9648387 Reactome R-HSA-9648387 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9648387.1 COSMIC COSV58688166 CDKN2A E33* p16INK4A E33* p16INK4A E27TER p16INK4A Glu33TER p16INK4A Glu33* CDKN2A E33TER CDKN2A Glu33TER CDKN2A Glu33* Reactome DB_ID: 9648393 33 EQUAL 1 EQUAL 32 EQUAL Reactome Database ID Release 77 9648393 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9648393 Reactome R-HSA-9648393 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9648393.1 COSMIC COSV58682729 CDKN2A E61* p16INK4A E61* p16INK4A E61TER p16INK4A Glu61TER p16INK4A Glu61* CDKN2A E61TER CDKN2A Glu61TER CDKN2A Glu61* Reactome DB_ID: 9648396 61 EQUAL 1 EQUAL 60 EQUAL Reactome Database ID Release 77 9648396 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9648396 Reactome R-HSA-9648396 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9648396.1 COSMIC COSV58683250 CDKN2A E69* p16INK4A E69* p16INK4A E69TER p16INK4A Glu69TER p16INK4A Glu69* CDKN2A E69TER CDKN2A Glu69TER CDKN2A Glu69* Reactome DB_ID: 9648397 69 EQUAL 1 EQUAL 68 EQUAL Reactome Database ID Release 77 9648397 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9648397 Reactome R-HSA-9648397 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9648397.1 COSMIC COSV58683264 COSMIC COSV58690247 CDKN2A P75* p16INK4A P75* p16INK4A P75TER p16INK4A Pro75TER p16INK4A Pro75* CDKN2A P75TER CDKN2A Pro75TER CDKN2A Pro75* Reactome DB_ID: 9648388 75 EQUAL 1 EQUAL 74 EQUAL Reactome Database ID Release 77 9648388 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9648388 Reactome R-HSA-9648388 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9648388.1 COSMIC COSM306135 CDKN2A Q50* p16INK4A Q50* p16INK4A Q50TER p16INK4A Gln50TER p16INK4A Gln50* CDKN2A Q50TER CDKN2A Gln50TER CDKN2A Gln50* Reactome DB_ID: 9648394 50 EQUAL L-glutamine removal MOD MOD:01637 1 EQUAL 49 EQUAL Reactome Database ID Release 77 9648394 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9648394 Reactome R-HSA-9648394 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9648394.1 COSMIC COSV58683786 COSMIC COSM53072 COSMIC COSV58717062 COSMIC COSV58696145 CDKN2A W15* p16INK4A W15* p16INK4A W15TER p16INK4A Trp15TER p16INK4A Trp15* CDKN2A W15TER CDKN2A Trp15TER CDKN2A Trp15* Reactome DB_ID: 9648395 15 EQUAL 1 EQUAL 14 EQUAL Reactome Database ID Release 77 9648395 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9648395 Reactome R-HSA-9648395 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9648395.1 COSMIC COSV58683123 COSMIC COSV58683138 CDKN2A Y44* p16INK4A Y44* p16INK4A Y44TER p16INK4A Tyr44TER p16INK4A Tyr44* CDKN2A Y44TER CDKN2A Tyr44TER CDKN2A Tyr44* Reactome DB_ID: 9648398 44 EQUAL L-tyrosine removal MOD 国防部:01649 1 EQUAL 43 EQUAL Reactome Database ID Release 77 9648398 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9648398 Reactome R-HSA-9648398 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9648398.1 CDKN2A A36fs*17 p16INK4A A36fs*17 p16INK4A Ala36fs*17 CDKN2A Ala36fs*17 p16INK4A A36fsTER17 p16INK4A Ala36fsTER17 CDKN2A A36fsTER17 CDKN2A Ala36fsTER17 Reactome DB_ID: 9648653 Replacement of residues 36 to 51 by RCPTHRIVTVGGRSRS 1 EQUAL 51 EQUAL Reactome Database ID Release 77 9648653 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9648653 Reactome R-HSA-9648653 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9648653.1 COSMIC COSV58691928 CDKN2A G23fs*3 p16INK4A G23fs*3 p16INK4A Gly23fs*3 CDKN2A Gly23fs*3 p16INK4A G23fsTER3 p16INK4A Gly23fsTER3 CDKN2A G23fsTER3 CDKN2A Gly23fsTER3 Reactome DB_ID: 9648652 Replacement of residues 23 to 24 by VG 1 EQUAL 24 EQUAL Reactome Database ID Release 77 9648652 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9648652 Reactome R-HSA-9648652 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9648652.1 COSMIC COSV58686555 CDKN2A L16fs*9 p16INK4A L16fs*9 p16INK4A Leu16fs*9 CDKN2A Leu16fs*9 p16INK4A L16fsTER9 p16INK4A Leu16fsTER9 CDKN2A L16fsTER9 CDKN2A Leu16fsTER9 Reactome DB_ID: 9648663 Replacement of residues 16 to 23 by PRPRPGVG 1 EQUAL 23 EQUAL Reactome Database ID Release 77 9648663 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9648663 Reactome R-HSA-9648663 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9648663.1 COSMIC COSV58683946 CDKN2A Y44fs*1 p16INK4A Y44fs*1 p16INK4A Tyr44fs*1 CDKN2A Tyr44fs*1 p16INK4A Y44fsTER1 p16INK4A Tyr44fsTER1 CDKN2A Y44fsTER1 CDKN2A Tyr44fsTER1 Reactome DB_ID: 9648664 Replacement of residues 44 to 44 1 EQUAL 43 EQUAL Reactome Database ID Release 77 9648664 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9648664 Reactome R-HSA-9648664 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9648664.1 COSMIC COSV58697475 COSMIC COSV58682773 COSMIC COSV58713131 COSMIC COSV58682773 CDKN2A L37fs*16 p16INK4A L37fs*16 p16INK4A Leu37fs*16 CDKN2A Leu37fs*16 p16INK4A L37fsTER16 p16INK4A Leu37fsTER16 CDKN2A L37fsTER16 CDKN2A Leu37fsTER16 Reactome DB_ID: 9648659 Replacement of residues 37 to 51 by RPTHRIVTVGGRSRS 1 EQUAL 51 EQUAL Reactome Database ID Release 77 9648659 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9648659 Reactome R-HSA-9648659 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9648659.1 COSMIC COSV58686404 CDKN2A N39fs*14 p16INK4A N39fs*14 p16INK4A Asn39fs*14 CDKN2A Asn39fs*14 p16INK4A N39fsTER14 p16INK4A Asn39fsTER14 CDKN2A N39fsTER14 CDKN2A Asn39fsTER14 Reactome DB_ID: 9648647 Replacement of residues 39 to 51 by THRIVTVGGRSRS 1 EQUAL 51 EQUAL Reactome Database ID Release 77 9648647 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9648647 Reactome R-HSA-9648647 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9648647.1 COSMIC COSV58688914 CDKN2A S7fs*8 p16INK4A S7fs*8 p16INK4A Ser7fs*8 CDKN2A Ser7fs*8 p16INK4A S7fsTER8 p16INK4A Ser7fsTER8 CDKN2A S7fsTER8 CDKN2A Ser7fsTER8 Reactome DB_ID: 9648651 Replacement of residues 7 to 13 by RQHGAFG 1 EQUAL 13 EQUAL Reactome Database ID Release 77 9648651 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9648651 Reactome R-HSA-9648651 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9648651.1 COSMIC COSV58693889 CDKN2A T18fs*15 p16INK4A T18fs*15 p16INK4A Thr18fs*15 CDKN2A Thr18fs*15 p16INK4A T18fsTER15 p16INK4A Thr18fsTER15 CDKN2A T18fsTER15 CDKN2A Thr18fsTER15 Reactome DB_ID: 9648655 Replacement of residues 18 to 31 by AGAAGGGGAAQRTE 1 EQUAL 31 EQUAL Reactome Database ID Release 77 9648655 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9648655 Reactome R-HSA-9648655 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9648655.1 COSMIC COSV58693372 CDKN2A T18fs*8 p16INK4A T18fs*8 p16INK4A Thr18fs*8 CDKN2A Thr18fs*8 p16INK4A T18fsTER8 p16INK4A Thr18fsTER8 CDKN2A T18fsTER8 CDKN2A Thr18fsTER8 Reactome DB_ID: 9648656 Replacement of residues 18 to 24 by RPRPGVG 1 EQUAL 24 EQUAL Reactome Database ID Release 77 9648656 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9648656 Reactome R-HSA-9648656 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9648656.1 COSMIC COSV58718256 COSMIC COSV58715219 CDKN2A W15fs*1 p16INK4A W15fs*1 p16INK4A Trp15fs*1 CDKN2A Trp15fs*1 p16INK4A W15fsTER1 p16INK4A Trp15fsTER1 CDKN2A W15fsTER1 CDKN2A Trp15fsTER1 Reactome DB_ID: 9648654 Replacement of residues 15 to 15 1 EQUAL 14 EQUAL Reactome Database ID Release 77 9648654 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9648654 Reactome R-HSA-9648654 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9648654.1 COSMIC COSV58700944 Reactome Database ID Release 77 9630804 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9630804 Reactome R-HSA-9630804 2 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9630804.2 Converted from EntitySet in Reactome CDK4,CDK6 Reactome DB_ID: 69209 CDK4 Cdk4 细胞分裂蛋白激酶4 (EC 2.7.1。-)(循环in-dependent kinase 4) (PSK-J3) (CDK4) Cell division protein kinase 4 Cyclin-dependent kinase 4 PSK-J3 Reactome DB_ID: 68330 UniProt:P11802 CDK4 CDK4 细胞周期蛋白的功能Ser / Thr-kinase组件D-CDK4(DC) complexes that phosphorylate and inhibit members of the retinoblastoma (RB) protein family including RB1 and regulate the cell-cycle during G(1)/S transition. Phosphorylation of RB1 allows dissociation of the transcription factor E2F from the RB/E2F complexes and the subsequent transcription of E2F target genes which are responsible for the progression through the G(1) phase. Hypophosphorylates RB1 in early G(1) phase. Cyclin D-CDK4 complexes are major integrators of various mitogenenic and antimitogenic signals. Also phosphorylates SMAD3 in a cell-cycle-dependent manner and represses its transcriptional activity. Component of the ternary complex, cyclin D/CDK4/CDKN1B, required for nuclear translocation and activity of the cyclin D-CDK4 complex.ACTIVITY REGULATION Both phosphorylation at Thr-172 and binding of a D-type cyclin are necessary for enzymatic activity. Full activation of the cyclin-D-CDK4 complex appears to require other factors such as recruitment of the substrate via a substrate recruitment motif, and/or formation of the CDKN1B ternary complex. Inhibited by INK4 family members. In resting cells, the non-tyrosine-phosphorylated form of CDKN1B prevents phosphorylation at Thr-172 and inactivation, while, in proliferating cells, tyrosine phosphorylation of CDKN1B allows phosphorylation of Thr-172 of CDK4 and subsequent activation.SUBUNIT Component of the D-CDK4 complex, composed of CDK4 and some D-type G1 cyclin (CCND1, CCND2 or CCND3). Interacts directly in the complex with CCND1, CCND2 or CCND3. Interacts with SEI1 and ZNF655. Forms a ternary complex, cyclin D-CDK4-CDKN1B, involved in modulating CDK4 enzymatic activity. Interacts directly with CDKN1B (phosphorylated on 'Tyr-88' and 'Tyr-89'); the interaction allows assembly of the cyclin D-CDK4 complex, Thr-172 phosphorylation, nuclear translocation and enhances the cyclin D-CDK4 complex activity. CDK4 activity is either inhibited or enhanced depending on stoichiometry of complex. The non-tyrosine-phosphorylated form of CDKN1B prevents T-loop phosphorylation of CDK4 producing inactive CDK4. Interacts (unphosphorylated form) with CDK2. Also forms ternary complexes with CDKN1A or CDKN2A. Interacts directly with CDKN1A (via its N-terminal); the interaction promotes the assembly of the cyclin D-CDK4 complex, its nuclear translocation and promotes the cyclin D-dependent enzyme activity of CDK4. Interacts with CCND1; the interaction is prevented with the binding of CCND1 to INSM1 during cell cycle progression. Probably forms a complex composed of chaperones HSP90 and HSP70, co-chaperones CDC37, PPP5C, TSC1 and client protein TSC2, CDK4, AKT, RAF1 and NR3C1; this complex does not contain co-chaperones STIP1/HOP and PTGES3/p23 (PubMed:29127155). Interacts with CEBPA (when phosphorylated) (PubMed:15107404). Interacts with FNIP1 and FNIP2 (PubMed:27353360).PTM Phosphorylation at Thr-172 is required for enzymatic activity. Phosphorylated, in vitro, at this site by CCNH-CDK7, but, in vivo, appears to be phosphorylated by a proline-directed kinase. In the cyclin D-CDK4-CDKN1B complex, this phosphorylation and consequent CDK4 enzyme activity, is dependent on the tyrosine phosphorylation state of CDKN1B. Thus, in proliferating cells, CDK4 within the complex is phosphorylated on Thr-172 in the T-loop. In resting cells, phosphorylation on Thr-172 is prevented by the non-tyrosine-phosphorylated form of CDKN1B.SIMILARITY Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. CDC2/CDKX subfamily. UniProt P11802 2 EQUAL 303 EQUAL Reactome Database ID Release 77 68330 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=68330 Reactome R-HSA-68330 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-68330.1 CDK6 Cdk6 Cell division protein kinase 6 (EC 2.7.1.-)(Serine/threonine-protein kinase) (PLSTIRE)(CDK6) Cell division protein kinase 6 Serine/threonine protein kinase PLSTIRE Reactome DB_ID: 68336 UniProt:Q00534 CDK6 CDK6 CDKN6 函数丝氨酸/ threonine-protein激酶参与in the control of the cell cycle and differentiation; promotes G1/S transition. Phosphorylates pRB/RB1 and NPM1. Interacts with D-type G1 cyclins during interphase at G1 to form a pRB/RB1 kinase and controls the entrance into the cell cycle. Involved in initiation and maintenance of cell cycle exit during cell differentiation; prevents cell proliferation and regulates negatively cell differentiation, but is required for the proliferation of specific cell types (e.g. erythroid and hematopoietic cells). Essential for cell proliferation within the dentate gyrus of the hippocampus and the subventricular zone of the lateral ventricles. Required during thymocyte development. Promotes the production of newborn neurons, probably by modulating G1 length. Promotes, at least in astrocytes, changes in patterns of gene expression, changes in the actin cytoskeleton including loss of stress fibers, and enhanced motility during cell differentiation. Prevents myeloid differentiation by interfering with RUNX1 and reducing its transcription transactivation activity, but promotes proliferation of normal myeloid progenitors. Delays senescence. Promotes the proliferation of beta-cells in pancreatic islets of Langerhans. May play a role in the centrosome organization during the cell cycle phases (PubMed:23918663).ACTIVITY REGULATION Inhibited by INK4 proteins (CDKN2C/p18-INK4c), aminopurvalanol, PD0332991, 4-(Pyrazol-4-yl)-pyrimidines and fisetin, a flavonol inhibitor. Activated by Thr-177 phosphorylation and Tyr-24 dephosphorylation (By similarity). Stimulated by cyclin from herpesvirus saimiri (V-cyclin/ECLF2). Rapidly down-regulated prior to cell differentiation (e.g. erythroid and osteoblast).SUBUNIT Interaction with D-type G1 cyclins. Cyclin binding promotes enzyme activation by phosphorylation at Thr-177 (By similarity). Binds to RUNX1, CDKN2D, FBXO7 and CDKN2C/p18-INK4c. Forms a cytoplasmic complex with Hsp90/HSP90AB1 and CDC37. FBXO7-binding promotes D-type cyclin binding. Interacts with Kaposi's sarcoma herpesvirus (KSHV) V-cyclin and herpesvirus saimiri (V-cyclin/ECLF2); the CDK6/V-cyclin complex phosphorylates NPM1 and thus lead to viral reactivation by reducing viral LANA levels.TISSUE SPECIFICITY Expressed ubiquitously. Accumulates in squamous cell carcinomas, proliferating hematopoietic progenitor cells, beta-cells of pancreatic islets of Langerhans, and neuroblastomas. Reduced levels in differentiating cells.INDUCTION Down-regulated in response to enterovirus 71 (EV71) infection. Induced by NANOG during S-phase entry.PTM Thr-177 phosphorylation and Tyr-24 dephosphorylation promotes kinase activity.POLYMORPHISM Genetic variations in CDK6 may influence stature as a quantitative trait, contributing to the stature quantitative trait locus 11 (STQTL11) [MIM:612223]. Adult height is an easily observable and highly heritable complex continuous trait. Because of this, it is a model trait for studying genetic influence on quantitative traits.MISCELLANEOUS Over-expressed in some leukemias and malignancies (including sarcoma, glioma, breast tumors, lymphoma and melanoma) as a consequence of nearby translocations.MISCELLANEOUS Enhances beta-cells engraftment in pancreatic islets of Langerhans of diabetic patients.SIMILARITY Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. CDC2/CDKX subfamily. UniProt Q00534 1 EQUAL 326 EQUAL Reactome Database ID Release 77 68336 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=68336 Reactome R-HSA-68336 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-68336.1 Reactome Database ID Release 77 69209 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=69209 Reactome R-HSA-69209 2 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-69209.2 Reactome Database ID Release 77 9630795 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9630795 Reactome R-HSA-9630795 2 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9630795.2 27899578 Pubmed 2017 COSMIC: somatic cancer genetics at high-resolution Forbes, Simon A Beare, David Boutselakis, Harry Bamford, Sally Bindal, Nidhi Tate, John Cole, Charlotte G Ward, Sari Dawson, Elisabeth Ponting, Laura Stefancsik, Raymund Harsha, Bhavana Kok, Chai Yin Jia, Mingming Jubb, Harry Sondka, Zbyslaw Thompson, Sam De, Tisham Campbell, Peter J Nucleic Acids Res. 45:D777-D783 10491434 Pubmed 1999 Biologic and biochemical analyses of p16(INK4a) mutations from primary tumors Yarbrough, W G Buckmire, R A Bessho, M Liu, E T J. Natl. Cancer Inst. 91:1569-74 9354451 Pubmed 1997 CDKN2A/p16 is inactivated in most melanoma cell lines Castellano, M Pollock, P M Walters, M K Sparrow, L E Down, L M Gabrielli, B G Parsons, P G Hayward, Nicholas K Cancer Res. 57:4868-75 9989830 Pubmed 1999 High frequency of p16INK4A gene alterations in hepatocellular carcinoma Liew, C T Li, H M Lo, K W Leow, C K Chan, J Y Hin, L Y Lau, W Y Lai, P B Lim, B K Huang, J Leung, W T Wu, S Lee, J C Oncogene 18:789-95 10389768 Pubmed 1999 Functional reassessment of P16 variants using a transfection-based assay Walker, G J Gabrielli, B G Castellano, M Hayward, Nicholas K Int. J. Cancer 82:305-12 10380936 Pubmed 1999 Loss of heterozygosity at chromosome 9p21 (INK4-p14ARF locus): homozygous deletions and mutations in the p16 and p14ARF genes in sporadic primary melanomas Kumar, R Smeds, J Lundh Rozell, B Hemminki, K Melanoma Res. 9:138-47 24659262 Pubmed 2014 CDKN2A unclassified variants in familial malignant melanoma: combining functional and computational approaches for their assessment Scaini, Maria Chiara Minervini, Giovanni Elefanti, Lisa Ghiorzo, Paola Pastorino, Lorenza Tognazzo, Silvia Agata, Simona Quaggio, Monica Zullato, Daniela Bianchi-Scarrà, Giovanna Montagna, Marco D'Andrea, Emma Menin, Chiara Tosatto, Silvio C E Hum. Mutat. 35:828-40 20340136 Pubmed 2010 Predicting functional significance of cancer-associated p16(INK4a) mutations in CDKN2A McKenzie, Heather A Fung, Carina Becker, Therese M Irvine, Mal Mann, GJ Kefford, Richard F Rizos, Helen Hum. Mutat. 31:692-701 17909018 Pubmed 2007 A CDKN2A mutation in familial melanoma that abrogates binding of p16INK4a to CDK4 but not CDK6 Jones, Rebecca Ruas, Margarida Gregory, Fiona Moulin, Stephanie Delia, Domenico Manoukian, Siranoush Rowe, Janice Brookes, Sharon Peters, Gordon Cancer Res. 67:9134-41 19260062 Pubmed 2009 Functional, structural, and genetic evaluation of 20 CDKN2A germ line mutations identified in melanoma-prone families or patients Kannengiesser, Caroline Brookes, Sharon del Arroyo, Anna Gutierrez Pham, Danielle Bombled, Johny Barrois, Michel Mauffret, Olivier 艾薇儿,玛丽e-Françoise M Chompret, Agnés Lenoir, Gilbert M Sarasin, Alain Hum. Mutat. 30:564-74 9328469 Pubmed 1997 Germline mutations of the CDKN2 gene in UK melanoma families Harland, M Meloni, R Gruis, N Pinney, E Brookes, S Spurr, N K Frischauf, A M Bataille, V Peters, G Cuzick, J Selby, P Bishop, D T Bishop, J N Hum. Mol. Genet. 6:2061-7 10498896 Pubmed 1999 Functional evaluation of tumour-specific variants of p16INK4a/CDKN2A: correlation with protein structure information Ruas, M Brookes, S 麦当劳,N问 Peters, G Oncogene 18:5423-34 21053367 Pubmed 2010 C-terminal domain of p16(INK4a) is adequate in inducing cell cycle arrest, growth inhibition and CDK4/6 interaction similar to the full length protein in HT-1080 fibrosarcoma cells Fahham, Najmeh Sardari, Soroush Ostad, Seyed Nasser Vaziri, Behrouz Ghahremani, Mohammad Hossein J. Cell. Biochem. 111:1598-606 11595726 Pubmed 2001 Functional impairment of melanoma-associated p16(INK4a) mutants in melanoma cells despite retention of cyclin-dependent kinase 4 binding Becker, T M Rizos, H Kefford, R F Mann, G J Clin. Cancer Res. 7:3282-8 8153634 Pubmed 1994 A cell cycle regulator potentially involved in genesis of many tumor types Kamb, A Gruis, N A Weaver-Feldhaus, J Liu, Q Harshman表示,K Tavtigian, S V Stockert, E Day, R S Johnson, B E Skolnick, M H Science 264:436-40 Reactome Database ID Release 77 9630794 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9630794 Reactome R-HSA-9630794 2 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9630794.2 15913553 Pubmed 2005 Impaired inhibition of NF-kappaB activity by melanoma-associated p16INK4a mutations Becker, T M Rizos, H de la Pena, A Leclercq, I A Woodruff, S Kefford, R F Mann, G J Biochem. Biophys. Res. Commun. 332:873-9 18843795 Pubmed 2008 p16INK4a-induced senescence is disabled by melanoma-associated mutations Haferkamp, Sebastian Becker, Therese M Scurr, Lyndee L Kefford, Richard F Rizos, Helen Aging Cell 7:733-45 Evasion of Oncogene Induced Senescence Due to Defective p16INK4A binding to CDK4 Missense mutations and small indels in the CDKN2A gene, which result in amino acid changes in p16INK4A that impair its ability to bind to CDK4, interfere with p16INK4A-mediated induction of cellular senescence in response to oncogenic signaling (Jones et al. 2007).
Loss-of-function mutations in p16INK4A can also contribute to cancer by interfering with p16INK4A-mediated inhibition of NFKB signaling (Becker et al. 2005). Authored: Orlic-Milacic, Marija, 2018-12-24 Reviewed: Bennett, Dorothy C, 2019-04-23 Reviewed: Nathan, Vaishnavi, 2019-06-03 Reviewed: Hayward, Nicholas K, 2019-06-03 Edited: Orlic-Milacic, Marija, 2019-05-07 LEFT-TO-RIGHT p16INK4A mutants do not bind CDK4 野生型p16INK4A分子能够形成一个复杂either CDK4 or CDK6 and prevent formation of catalytically active CDK complexes consisting of CDK4 or CDK6 and D-type cyclins (CCND). Several CDKN2A missense mutations found in cancer lead to amino acid substitutions in p16INK4A that impair binding of p16INK4A mutants to CDK4 while binding of these mutants to CDK6 is preserved. Functionally tested p16INK4A mutants that bind to CDK6 but not to CDK4 are:

p16INK4A R24P (Harland et al. 1997, Becker et al. 2001, Jones et al. 2007, McKenzie et al. 2010)
p16INK4A E88K (Ruas et al. 1999)
p16INK4A R112_L113insR (Ruas et al. 1999)

p16INK4A R24P is partially functional in inhibiting cellular proliferation (Jones et al. 2007), but its activity is severely reduced (Becker et al. 2001). Partial functionality in inhibition of cellular proliferation is also attributed to p16INK4A E88K (Ruas et al. 1999), but experimental evidence is lacking. The ability of p16INK4A R112_L113insR to inhibit cellular proliferation has not been tested.
A number of p16INK4A missense mutants have only been tested for their ability to bind to CDK4, but not CDK6. Mutants impaired in CDK4 binding whose binding to CDK6 has not been established include:

p16INK4A T18_A19dup (Kannengiesser et al. 2009)
p16INK4A G23D (Scaini et al. 2009, Kannengiesser et al. 2009, McKenzie et al. 2010)
p16INK4A G35A (Kannengiesser et al. 2009, McKenzie et al. 2010, Scaini et al. 2014)
p16INK4A G35V (Kannengiesser et al. 2009, McKenzie et al. 2010, Scaini et al. 2014)
p16INK4A A60R (Kannengiesser et al. 2009, McKenzie et al. 2010)
p16INK4A A60V (Kannengiesser et al. 2009, McKenzie et al. 2010)
p16INK4A G67_N71del (Kannengiesser et al. 2009)
p16INK4A D74Y (Kannengiesser et al. 2009)
p16INK4A T77P (Kannengiesser et al. 2009)
p16INK4A R80P (Kannengiesser et al. 2009)
p16INK4A L97R (Kannengiesser et al. 2009, McKenzie et al. 2010)
p16INK4A R99P (Kannengiesser et al. 2009, McKenzie et al. 2010)

p16INK4A G23D shows a reduced ability to prevent CDK4-mediated phosphorylation of RB1 (Scaini et al. 2009) and to inhibit cellular proliferation (Scaini et al. 2014). Impairment of ability to inhibit cellular proliferation was also demonstrated for p16INK4A G35A and p16INK4A G35V (Scaini et al. 2014), p16INK4A D74Y (Scaini et al. 2014), p16INK4A R80P (Jenkins et al. 2013) and p16INK4A R99P (Jenkins et al. 2013).
Based on sequence change similarity, the following p16INK4A mutants that have not been tested for their ability to bind to CDK4 or CDK6, but have been reported in cancer and predicted to be pathogenic ( COSMIC database: Forbes et al. 2017) are annotated as candidates:

p16INK4A G23S
p16INK4A G23V
p16INK4A G35E
p16INK4A G35R
p16INK4A G35W
p16INK4A A60E
p16INK4A A60S
p16INK4A T77S
p16INK4A L97P

p16INK4A G23S and p16INK4A G23V show reduced ability to inhibit cellular proliferation (Scaini et al. 2014). p16INK4A G35E and p16INK4A G35R were shown to be markedly impaired in their ability to inhibit cellular proliferation, while p16INK4A G35W is somewhat impaired (Scaini et al. 2014). p16INK4A D74N (p16INK4A Asp74Ans) was not annotated because, while it is predicted to be pathogenic, it retains the ability to bind CDK4 and CDK6 (Yarbrough et al. 1999).
Mechanistic consequences of some p16INK4A mutations have not yet been elucidated. For example, substitution of alanine to proline at position 36, which is a consequence of a missense mutation in the exon 1alpha of CDKN2A, thus affecting only p16INK4A, results in expression of a mutant p16INK4A A36P protein. p16INK4A A36P retains the ability to bind to CDK4 (Becker et al. 2001, although not reproduced by McKenzie et al. 2010), but is not able to consistently inhibit CDK4-mediated phosphorylation of RB1 (Haferkamp et al. 2008), and is impaired in its ability to induce cell cycle arrest (Becker et al. 2001, Haferkamp et al. 2008). Another study shows that p16INK4A A36P retains cell cycle arrest-inducing ability, but is impaired in its ability to regulate intracellular oxidative stress (Jenkins et al. 2013). Authored: Orlic-Milacic, Marija, 2018-12-24 Reviewed: Bennett, Dorothy C, 2019-04-23 Reviewed: Nathan, Vaishnavi, 2019-06-03 Reviewed: Hayward, Nicholas K, 2019-06-03 Converted from EntitySet in Reactome p16INK4A LoF mutants (CDK4) Reactome DB_ID: 9630826 p16INK4A R24P p16INK4A Arg24Pro Reactome DB_ID: 9630828 24 EQUAL 1 EQUAL 156 EQUAL Reactome Database ID Release 77 9630828 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9630828 Reactome R-HSA-9630828 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9630828.1 COSMIC COSM36170 COSMIC COSV58704208 CDKN2A G23D p16INK4A G23D p16INK4A分子Gly23Asp CDKN2A Gly23Asp Reactome DB_ID: 9630892 23 EQUAL 1 EQUAL 156 EQUAL Reactome Database ID Release 77 9630892 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9630892 Reactome R-HSA-9630892 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9630892.1 COSMIC COSV58702991 COSMIC COSM7339006 CDKN2A G35A p16INK4A G35A p16INK4A Gly35Ala CDKN2A Gly35Ala Reactome DB_ID: 9631306 35 EQUAL 1 EQUAL 156 EQUAL Reactome Database ID Release 77 9631306 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9631306 Reactome R-HSA-9631306 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9631306.1 COSMIC COSV58690595 CDKN2A G35V p16INK4A G35V p16INK4A分子Gly35Val CDKN2A Gly35Val Reactome DB_ID: 9631308 35 EQUAL 1 EQUAL 156 EQUAL Reactome Database ID Release 77 9631308 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9631308 Reactome R-HSA-9631308 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9631308.1 COSMIC COSV58690447 CDKN2A D74Y p16INK4A D74Y p16INK4A Asp74Tyr CDKN2A Asp74Tyr Reactome DB_ID: 9632088 74 EQUAL 1 EQUAL 156 EQUAL Reactome Database ID Release 77 9632088 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9632088 Reactome R-HSA-9632088 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9632088.1 COSMIC COSV58683415 CDKN2A T18_A19dup p16INK4A T18_A19dup p16INK4A Thr18_Ala19dup CDKN2A Thr18_Ala19dup Reactome DB_ID: 9632192 Insertion of residues 18 to 19 at 20 from UniProt:P42771 CDKN2A 20 EQUAL 1 EQUAL 156 EQUAL Reactome Database ID Release 77 9632192 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9632192 Reactome R-HSA-9632192 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9632192.1 COSMIC COSV58717622 CDKN2A A60V p16INK4A A60V p16INK4A Ala60Val CDKN2A Ala60Val Reactome DB_ID: 9632212 60 EQUAL 1 EQUAL 156 EQUAL Reactome Database ID Release 77 9632212 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9632212 Reactome R-HSA-9632212 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9632212.1 COSMIC COSV58685686 CDKN2A A60R p16INK4A A60R p16INK4A Ala60Arg CDKN2A Ala60Arg Reactome DB_ID: 9632216 60 EQUAL 1 EQUAL 156 EQUAL Reactome Database ID Release 77 9632216 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9632216 Reactome R-HSA-9632216 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9632216.1 COSMIC COSV58685686 CDKN2A G67_N71del p16INK4A G67_N71del p16INK4A Gly67_Asn71del CDKN2A Gly67_Asn71del Reactome DB_ID: 9632252 Deletion of residues 67 to 71 1 EQUAL 156 EQUAL Reactome Database ID Release 77 9632252 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9632252 Reactome R-HSA-9632252 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9632252.1 CDKN2A T77P p16INK4A T77P p16INK4A Thr77Pro CDKN2A Thr77Pro Reactome DB_ID: 9632257 77 EQUAL L-threonine removal MOD 国防部:01647 1 EQUAL 156 EQUAL Reactome Database ID Release 77 9632257 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9632257 Reactome R-HSA-9632257 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9632257.1 CDKN2A R80P p16INK4A R80P p16INK4A Arg80Pro CDKN2A Arg80Pro Reactome DB_ID: 9632270 80 EQUAL 1 EQUAL 156 EQUAL Reactome Database ID Release 77 9632270 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9632270 Reactome R-HSA-9632270 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9632270.1 CDKN2A L97R p16INK4A L97R p16INK4A Leu97Arg CDKN2A Leu97Arg Reactome DB_ID: 9632512 97 EQUAL L-leucine removal MOD MOD:01641 1 EQUAL 156 EQUAL Reactome Database ID Release 77 9632512 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9632512 Reactome R-HSA-9632512 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9632512.1 COSMIC COSV58684740 CDKN2A R99P p16INK4A R99P p16INK4A Arg99Pro CDKN2A Arg99Pro Reactome DB_ID: 9632531 99 EQUAL 1 EQUAL 156 EQUAL Reactome Database ID Release 77 9632531 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9632531 Reactome R-HSA-9632531 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9632531.1 COSMIC COSV58689257 CDKN2A E88K p16INK4A E88K p16INK4A分子Glu88Lys CDKN2A Glu88Lys Reactome DB_ID: 9632548 88 EQUAL 1 EQUAL 156 EQUAL Reactome Database ID Release 77 9632548 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9632548 Reactome r - hsa - 9632548 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9632548.1 COSMIC COSV58683670 CDKN2A R112_L113insR p16INK4A R112_L113insR p16INK4A Arg112_Leu113insArg CDKN2A Arg112_Leu113insR Reactome DB_ID: 9632566 Insertion of residues 112 to 112 at 113 from UniProt:P42771 CDKN2A 113 EQUAL 1 EQUAL 156 EQUAL Reactome Database ID Release 77 9632566 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9632566 Reactome R-HSA-9632566 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9632566.1 CDKN2A G23S p16INK4A G23S p16INK4A Gly23Ser CDKN2A Gly23Ser Reactome DB_ID: 9631163 23 EQUAL 1 EQUAL 156 EQUAL Reactome Database ID Release 77 9631163 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9631163 Reactome R-HSA-9631163 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9631163.1 COSMIC COSV58709325 COSMIC COSV58710074 CDKN2A G23V p16INK4A G23V p16INK4A Gly23Val CDKN2A Gly23Val Reactome DB_ID: 9631157 23 EQUAL 1 EQUAL 156 EQUAL Reactome Database ID Release 77 9631157 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9631157 Reactome R-HSA-9631157 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9631157.1 COSMIC COSV58684053 CDKN2A G35E p16INK4A G35E p16INK4A Gly35Glu CDKN2A Gly35Glu Reactome DB_ID: 9631314 35 EQUAL 1 EQUAL 156 EQUAL Reactome Database ID Release 77 9631314 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9631314 Reactome R-HSA-9631314 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9631314.1 COSMIC COSV58726978 CDKN2A G35R p16INK4A G35R p16INK4A Gly35Arg CDKN2A Gly35Arg Reactome DB_ID: 9631316 35 EQUAL 1 EQUAL 156 EQUAL Reactome Database ID Release 77 9631316 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9631316 Reactome R-HSA-9631316 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9631316.1 COSMIC COSV58691471 CDKN2A G35W p16INK4A G35W p16INK4A Gly35Trp CDKN2A Gly35Trp Reactome DB_ID: 9631328 35 EQUAL 1 EQUAL 156 EQUAL Reactome Database ID Release 77 9631328 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9631328 Reactome R-HSA-9631328 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9631328.1 COSMIC COSV58712281 CDKN2A A60S p16INK4A A60S p16INK4A Ala60Ser CDKN2A Ala60Ser Reactome DB_ID: 9632206 60 EQUAL 1 EQUAL 156 EQUAL Reactome Database ID Release 77 9632206 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9632206 Reactome R-HSA-9632206 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9632206.1 COSMIC COSV58704370 CDKN2A A60E p16INK4A A60E p16INK4A Ala60Glu CDKN2A Ala60Glu Reactome DB_ID: 9632202 60 EQUAL 1 EQUAL 156 EQUAL Reactome Database ID Release 77 9632202 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9632202 Reactome R-HSA-9632202 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9632202.1 COSMIC COSV58692021 CDKN2A T77S p16INK4A T77S p16INK4A Thr77Ser CDKN2A Thr77Ser Reactome DB_ID: 9632256 77 EQUAL 1 EQUAL 156 EQUAL Reactome Database ID Release 77 9632256 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9632256 Reactome R-HSA-9632256 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9632256.1 COSMIC COSV58727079 CDKN2A L97P p16INK4A L97P p16INK4A Leu97Pro CDKN2A Leu97Pro Reactome DB_ID: 9632523 97 EQUAL 1 EQUAL 156 EQUAL Reactome Database ID Release 77 9632523 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9632523 Reactome R-HSA-9632523 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9632523.1 COSMIC COSV58691600 Reactome Database ID Release 77 9630826 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9630826 Reactome R-HSA-9630826 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9630826.1 Reactome Database ID Release 77 9630792 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9630792 Reactome R-HSA-9630792 2 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9630792.2 19712690 Pubmed 2009 Functional impairment of p16(INK4A) due to CDKN2A p.Gly23Asp missense mutation Scaini, Maria Chiara Rossi, Elisabetta de Siqueira Torres, Paula Lobao Antunes Zullato, Daniela Callegaro, Monia Casella, Cinzia Quaggio, Monica Agata, Simona Malacrida, Sandro Chiarion-Sileni, Vanna Vecchiato, Antonella Alaibac, Mauro Montagna, Marco Mann, GJ Menin, Chiara D'Andrea, Emma Mutat. Res. 671:26-32 Reactome Database ID Release 77 9630791 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9630791 Reactome R-HSA-9630791 2 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9630791.2 Reactome Database ID Release 77 9630750 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9630750 Reactome R-HSA-9630750 3 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9630750.3 7585152 Pubmed 1995 5' CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers Merlo, Adrian Herman, James G Mao, Li Lee, Daniel J Gabrielson, Edward Burger, Peter C Baylin, Stephen B Sidransky, David Nat. Med. 1:686-92 10360174 Pubmed 1999 Mutations in human ARF exon 2 disrupt its nucleolar localization and impair its ability to block nuclear export of MDM2 and p53 Zhang, Y Xiong, Y Mol. Cell 3:579-91 24136988 Pubmed 2014 The molecular balancing act of p16(INK4a) in cancer and aging LaPak, Kyle M Burd, Christin E Mol. Cancer Res. 12:167-83 22020327 Pubmed 2012 Parallel pathways in RAF-induced senescence and conditions for its reversion Jeanblanc, M Ragu, S Gey, C Contrepois, K Courbeyrette, R Thuret, J-Y Mann, C Oncogene 31:3072-85 15761864 Pubmed 2005 Intronic sequence variants of the CDKN2A gene in melanoma pedigrees Harland, Mark Taylor, Claire F Bass, Sylvia Churchman, Michael Randerson-Moor, Juliette A Holland, Elizabeth A Mann, GJ Bishop, D Timothy Newton Bishop, Julia A Genes Chromosomes Cancer 43:128-36 20473920 Pubmed 2011 Prognostic significance of CDKN2A (p16) promoter methylation and loss of expression in 902 colorectal cancers: Cohort study and literature review Shima, Kaori Nosho, Katsuhiko Baba, Yoshifumi Cantor, Mami Meyerhardt, Jeffrey A Giovannucci, Edward L Fuchs, Charles S Ogino, Shuji Int. J. Cancer 128:1080-94 8589035 Pubmed 1995 Frequent mutations of CDKN2 in primary pancreatic adenocarcinomas Bartsch, D Shevlin, D W Tung, W S Kisker, O Wells, S A Goodfellow, P J Genes Chromosomes Cancer 14:189-95 27812880 Pubmed 2017 Detection of Oncogene-Induced Senescence In Vivo Baek, Kwan-Hyuck Ryeom, Sandra Methods Mol. Biol. 1534:185-198 26105537 Pubmed 2015 Forging a signature of in vivo senescence Sharpless, Norman E Sherr, Charles J Nat. Rev. Cancer 15:397-408 10541553 Pubmed 1999 INK4a/ARF mutations accelerate lymphomagenesis and promote chemoresistance by disabling p53 Schmitt, C A McCurrach, M E de Stanchina, E Wallace-Brodeur, R R Lowe, S W Genes Dev. 13:2670-7 11726555 Pubmed 2001 深intronic突变CDKN2A w相关联ith disease in a subset of melanoma pedigrees Harland, M Mistry, S Bishop, D T Bishop, J A Hum. Mol. Genet. 10:2679-86 11477665 Pubmed 2001 Mutation analysis of the CDKN2A promoter in Australian melanoma families Pollock, P M Stark, M S Palmer, J M Walters, M K Aitken, J F Martin, N G Hayward, N K Genes Chromosomes Cancer 32:89-94 20016279 Pubmed 2010 Tumor suppression by ARF: gatekeeper and caretaker Dominguez-Brauer, Carmen Brauer, Patrick M Chen, Yi-Ju Pimkina, Julia Raychaudhuri, Pradip Cell Cycle 9:86-9 7553621 Pubmed 1995 Inactivation of the CDKN2/p16/MTS1 gene is frequently associated with aberrant DNA methylation in all common human cancers Herman, James G Merlo, Adrian Mao, Li Lapidus, Rena G Issa, Jean-Pierre J Davidson, Nancy E Sidransky, David Baylin, Stephen B Cancer Res. 55:4525-30 9916806 Pubmed 1999 Mutation of the CDKN2A 5' UTR creates an aberrant initiation codon and predisposes to melanoma Liu, L Dilworth, D Gao, L Monzon, J Summers, A Lassam, N Hogg, D Nat. Genet. 21:128-32 10854221 Pubmed 2000 INK4a/ARF locus alterations in human non-Hodgkin's lymphomas mainly occur in tumors with wild-type p53 gene Pinyol, M Hernández, L Martínez, A Cobo, F Hernández, S Beà, S López-Guillermo, A Nayach, I Palacín, A 纳达尔, Fernández, P L Montserrat, E Cardesa, A Campo, E Am. J. Pathol. 156:1987-96 15937071 Pubmed 2006 Comprehensive analysis of CDKN2A (p16INK4A/p14ARF) and CDKN2B genes in 53 melanoma index cases considered to be at heightened risk of melanoma Laud, K Marian, C Avril, M F Barrois, M Chompret, A Goldstein, A M Tucker, M A Clark, P A Peters, G Chaudru, V Demenais, F Spatz, A Smith, M W Lenoir, G M Bressac-de Paillerets, B J. Med. Genet. 43:39-47 11485924 Pubmed 2001 Alterations of the tumor suppressor genes CDKN2A (p16(INK4a)), p14(ARF), CDKN2B (p15(INK4b)), and CDKN2C (p18(INK4c)) in atypical and anaplastic meningiomas Boström, J Meyer-Puttlitz, B Wolter, M Blaschke, B Weber, R G Lichter, P Ichimura, K Collins, V P Reifenberger, G Am. J. Pathol. 159:661-9 21775818 Pubmed 2011 The meaning of p16(ink4a) expression in tumors: functional significance, clinical associations and future developments Witkiewicz, Agnieszka K Knudsen, Karen E Dicker, Adam P Knudsen, Erik S Cell Cycle 10:2497-503 7553622 Pubmed 1995 Methylation of the 5' CpG island of the p16/CDKN2 tumor suppressor gene in normal and transformed human tissues correlates with gene silencing Gonzalez-Zulueta, Mirella Bender, Christina M Yang, Allen S Nguyen, TuDung Beart, Robert W Van Tornout, Jan M Jones, Peter A Cancer Res. 55:4531-5 26997276 Pubmed 2016 Evasion of Cell Senescence Leads to Medulloblastoma Progression Tamayo-Orrego, Lukas Wu, Chia-Lun Bouchard, Nicolas Khedher, Ahmed Swikert, Shannon M Remke, Marc Skowron, Patryk Taylor, Michael D Charron, Frédéric Cell Rep 14:2925-37 18538737 Pubmed 2008 Mitochondrial p32 is a critical mediator of ARF-induced apoptosis Itahana, Koji Zhang, Yanping Cancer Cell 13:542-53 10541552 Pubmed 1999 Disruption of the ARF-Mdm2-p53 tumor suppressor pathway in Myc-induced lymphomagenesis Eischen, C M Weber, J D Roussel, M F Sherr, CJ Cleveland, J L Genes Dev. 13:2658-69 9205067 Pubmed 1997 p16INK4a promoter is hypermethylated at a high frequency in esophageal adenocarcinomas Wong, David J Barrett, Michael T Stöger, Reinhard Emond, Mary J Reid, Brian J Cancer Res. 57:2619-22 Evasion of Oncogene Induced Senescence Due to p14ARF Defects 在细胞培养中,p14ARF (CDKN2A成绩单4,CDKN2A-4, ARF), one of the two main protein products of the CDKN2A gene, contributes to oncogene induced senescence by stabilizing TP53 (p53). The function of p14ARF in p53 stabilization through sequestration of MDM2, a p53 ubiquitin ligase, depends on the nuclear localization of p14ARF and its ability to interact with MDM2. The nuclear localization signal and the MDM2 interaction domain map to the first 15 amino acids of the N-terminus of p14ARF. This region is encoded by the p14ARF-specific exon 1beta of CDKN2A. An independent MDM2-binding domain localized to the C-terminus of p14ARF (Lohrum et al. 2000). Insertion of 16 nucleotides in exon 1beta results in a frameshift truncation of p14ARF, responsible for a familial melanoma syndrome in which the p16INK4A product of the CDKN2A gene is unaffected. This mutation is rare and has so far been reported in one family only. The mutant protein, p14ARF R21RfsTER47 has the nucleotide localization signal and the N-terminal MDM2 interaction region preserved, but is unable to translocate from the cytosol to the nucleus, possibly due to aberrant conformation (Rizos, Puig et al. 2001), and also lacks the C-terminal MDM2 interaction region. Relocation of wild type p14ARF to the cytosol has been observed in melanoma (Rizos, Darmanian et al. 2001) and aggressive thyroid papillary carcinoma (Ferru et al. 2006). Genomic deletion of exon 1beta, with exons 1alpha, 2 and 3 intact, has been reported in about 30% of melanoma cases with genomic deletions involving the CDKN2A locus (Freedberg et al. 2008). Several different familial melanoma germline mutations map to the exon 1beta splice donor site (Harland et al. 2005).
The ability of p14ARF to localize to the nucleolus also plays a role in p14ARF-mediated stabilization of p53. Mutations in exon 2 of the CDKN2A gene can lead to missense mutations in p14ARF that affect its nucleolar localization and p53 stabilization, but the exact mechanism has not been fully elucidated (Zhang and Xiong 1999, reviewed by Fontana et al. 2019). Authored: Orlic-Milacic, Marija, 2019-06-28 综述:rizo,海伦,2019-07-08 Reviewed: Bennett, Dorothy C, 2019-08-12 Edited: Orlic-Milacic, Marija, 2019-07-16 Edited: Orlic-Milacic, Marija, 2019-08-14 LEFT-TO-RIGHT p14ARF mutant does not translocate to the nucleus A germline mutation affecting exon 1beta of the CDKN2A locus is associated with a familial melanoma syndrome. The mutation represents an insertion of 16 nucleotides (CGGCCCGCCGCGAGTG) between coding bases 60 and 61 in exon 1beta. This insertion results in a frameshift, starting at arginine codon at position 21 of p14ARF and ending with a premature stop codon at position 67. The mutant protein p14ARF R21RfsTER47 (p14ARF 60ins16) is unable to translocate to the nucleus and stabilize TP53 (Rizos, Puig et al. 2001). Authored: Orlic-Milacic, Marija, 2019-06-28 综述:rizo,海伦,2019-07-08 Reviewed: Bennett, Dorothy C, 2019-08-12 Edited: Orlic-Milacic, Marija, 2019-07-16 Edited: Orlic-Milacic, Marija, 2019-08-14 p14ARF 60ins16 p14ARF R21RfsTER47 CDKN2A-4 R21RfsTER47 p14ARF Arg21ArgfsTER47 CDKN2A-4 Arg21ArgfsTER47 Reactome DB_ID: 9646285 UniProt:Q8N726 CDKN2A CDKN2A CDKN2 MLM FUNCTION Capable of inducing cell cycle arrest in G1 and G2 phases. Acts as a tumor suppressor. Binds to MDM2 and blocks its nucleocytoplasmic shuttling by sequestering it in the nucleolus. This inhibits the oncogenic action of MDM2 by blocking MDM2-induced degradation of p53 and enhancing p53-dependent transactivation and apoptosis. Also induces G2 arrest and apoptosis in a p53-independent manner by preventing the activation of cyclin B1/CDC2 complexes. Binds to BCL6 and down-regulates BCL6-induced transcriptional repression. Binds to E2F1 and MYC and blocks their transcriptional activator activity but has no effect on MYC transcriptional repression. Binds to TOP1/TOPOI and stimulates its activity. This complex binds to rRNA gene promoters and may play a role in rRNA transcription and/or maturation. Interacts with NPM1/B23 and promotes its polyubiquitination and degradation, thus inhibiting rRNA processing. Interacts with COMMD1 and promotes its 'Lys63'-linked polyubiquitination. Interacts with UBE2I/UBC9 and enhances sumoylation of a number of its binding partners including MDM2 and E2F1. Binds to HUWE1 and represses its ubiquitin ligase activity. May play a role in controlling cell proliferation and apoptosis during mammary gland development. Isoform smARF may be involved in regulation of autophagy and caspase-independent cell death; the short-lived mitochondrial isoform is stabilized by C1QBP.SUBUNIT Does not interact with cyclins, CDK1, CDK2, CDK4, CDK5 or CDK6. Binds to BCL6, E2F1, HUWE1, MDM2, MYC, NPM1/B23, TOP1/TOPOI and UBE2I/UBC9. Interacts with TBRG1 and COMMD1. Interacts with CDKN2AIP and E4F1. Interacts with CDK5RAP3 and MDM2; form a ternary complex involved in regulation of p53/TP53 (PubMed:16173922). Isoform smARF interacts with C1QBP. Interacts with NOP53; the interaction is direct and promotes ARF nucleoplasmic relocalization and ubiquitin-mediated proteasomal degradation (PubMed:27323397).PTM Ubiquitinated in normal cells by TRIP12 via the ubiquitin fusion degradation (UFD) pathway, a process that mediates ubiquitination at the N-terminus, regardless of the absence of lysine residues. Ubiquitination leads to its proteasomal degradation. In cancer cells, however, TRIP12 is located in a different cell compartment, preventing ubiquitination and degradation.CAUTION The proteins described here are encoded by the gene CDKN2A, but are completely unrelated in terms of sequence and function to cyclin-dependent kinase inhibitor 2A (AC P42771) which is encoded by the same gene. UniProt Q8N726 Replacement of residues 21 to 132 by RPAASEGFRGSHPAAHGGVGSARGARRCGPRADATEEPASRAAAAS 1 EQUAL 66 EQUAL Reactome Database ID Release 77 9646285 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9646285 Reactome R-HSA-9646285 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9646285.1 Reactome Database ID Release 77 9646295 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9646295 Reactome R-HSA-9646295 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9646295.1 11571653 Pubmed 2001 A melanoma-associated germline mutation in exon 1beta inactivates p14ARF Rizos, H Puig, S Badenas, C Malvehy, J Darmanian, A P Jiménez, L Milà, M Kefford, R F Oncogene 20:5543-7 Reactome Database ID Release 77 9646303 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9646303 Reactome R-HSA-9646303 2 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9646303.2 17117177 Pubmed 2006 The status of CDKN2A alpha (p16INK4A) and beta (p14ARF) transcripts in thyroid tumour progression Ferru, A Fromont, G Gibelin, H Guilhot, J Savagner, F Tourani, J M Kraimps, J L Larsen, C J Karayan-Tapon, Lucie Br. J. Cancer 95:1670-7 11518711 Pubmed 2001 Mutations in the INK4a/ARF melanoma susceptibility locus functionally impair p14ARF Rizos, H Darmanian, A P Holland, E A Mann, G J Kefford, R F J. Biol. Chem. 276:41424-34 18505964 Pubmed 2008 Frequent p16-independent inactivation of p14ARF in human melanoma Freedberg, Daniel E Rigas, Sushila H Russak, Julie Gai, Weiming Kaplow, Margarita Osman, Iman Turner, Faye Randerson-Moor, Juliette A Houghton, Alan Busam, Klaus Timothy Bishop, D Bastian, BC Newton-Bishop, Julia A Polsky, David J. Natl. Cancer Inst. 100:784-95 15856016 Pubmed 2005 A mutation hotspot at the p14ARF splice site Harland, Mark Taylor, Claire F Chambers, Philip A Kukalizch, Kairen Randerson-Moor, Juliette A Gruis, Nelleke A de Snoo, Femke A ter Huurne, Jeanet A C Goldstein, Alisa M Tucker, Margaret A Bishop, D Timothy Bishop, Julia A Newton Oncogene 24:4604-8 30836703 Pubmed 2019 Dual Role of the Alternative Reading Frame ARF Protein in Cancer Fontana, Rosa Ranieri, Michela La Mantia, Girolama Vivo, Maria Biomolecules 9: 10801444 Pubmed 2000 Contribution of two independent MDM2-binding domains in p14(ARF) to p53 stabilization Lohrum, M A Ashcroft, M Kubbutat, M H Vousden, K H Curr. Biol. 10:539-42 Evasion of Oxidative Stress Induced Senescence Due to p16INK4A Defects CDKN2A基因由四个外显子,外显子1β, exon 1alpha, exon 2 and exon 3, going from the proximal to the distal gene end. There are two promoters in the CDKN2A gene locus. The promoter located between exons 1beta and 1alpha regulates transcription of the p16INK4A mRNA, which consists of exon 1alpha, exon 2 and exon 3 (only partially translated), and encodes a cyclin-dependent kinase inhibitor p16INK4A (also known as CDKN2A isoform 1, p16, INK4A, CDKN2A, CDK4I or MTS-1). The promoter located upstream of exon 1beta regulates transcription of the p14ARF mRNA, which consists of exon 1beta, exon 2 (partially translated) and exon 3 (untranslated). The p14ARF mRNA is translated in a different reading frame from the p16INK4A mRNA and produces the tumor suppressor ARF (also known as p14ARF or CDKN2A isoform 4), an inhibitor of MDM2 E3 ubiquitin ligase-mediated degradation of TP53 (p53).
Wild type p16INK4A is able to form a complex with either CDK4 or CDK6 and prevent formation of catalytically active CDK complexes consisting of CDK4 or CDK6 and D-type cyclins (CCND). Thus, p16INK4A prevents hyperphosphorylation of RB-family proteins, required for initiation of DNA replication in RB1-competent cells. Expression of p16INK4A increases in response to oxidative stress, leading to cellular senescence (programmed cell cycle arrest) under conditions of prolonged oxidative stress. Loss-of-function of p16INK4A frequently occurs in cancer, usually through loss of p16INK4A protein expression due to promoter hypermethylation or CDKN2A gene deletion (Merlo et al. 1995, Herman et al. 1995, Gonzalez-Zulueta et al. 1995, Wong et al. 1997, Witkiewicz et al. 2011, Shima et al. 2011, Tamayo-Orrego et al. 2016). Missense, nonsense and frameshift mutations in the CDKN2A locus can also impair p16INK4A function through expression of non-functional substitution mutants or truncated proteins (Kamb et al. 1994, Bartsch et al. 1995, Castellano et al. 1997). Germline intronic CDKN2A mutations that create aberrant splicing sites and result in expression of non-functional splicing variants of p16INK4A have been reported in familial melanoma (Harland et al. 2001, Harland et al. 2005). A CDKN2A gene mutation in the region encoding the 5'UTR of p16INK4A, reported in familial melanoma, creates a novel translation start codon and diminishes translation from the wild type start codon (Liu et al. 1999). However, mutations in the non coding regions of the CDKN2A gene are rare (Pollock et al. 2001).
p16INK4A defects enable cancerous cells to evade cell cycle arrest and senescence under prolonged oxidative stress (Tanaka et al. 1999, Chen 2000, Chen et al. 2004, Vurusaner et al. 2012, Rayess et al. 2012, LaPak and Burd 2014, Sharpless and Sherr 2015, Zhang et al. 2017). A cell cycle-independent role of p16INK4A in regulation of intracellular oxidative stress has been reported (Jenkins et al. 2011, Vurusaner et al. 2012, Jenkins et al. 2013).
Genomic deletions in the CDKN2A locus affect p14ARF, unless they are limited to exon 1alpha. The p14ARF promoter can also be hypermethylated in cancer, leading to loss of p14ARF expression. Some missense mutations occurring in exon 2 of the CDKN2A gene affect the p14ARF protein sequence. However, p14ARF mutants usually appear to be less functionally compromised than their p16INK4A counterparts. Most functional tests on p14ARF mutants examine the effect of mutations on MDM2 binding and TP53-mediated transcription of CDKN1A (p21), as well as sub-nuclear localization of p14ARF (Zhang and Xiong 1999, Schmitt et al. 1999, Eischen et al. 1999, Pinyol et al. 2000, Bostrom et al. 2001, Laud et al. 2006). Still, there are poorly explored functions of p14ARF that may be significantly affected in mutant p14ARF proteins detected in cancer (Itahana and Zhang 2008, Dominguez-Brauer et al. 2010). Authored: Orlic-Milacic, Marija, 2018-12-24 Reviewed: Bennett, Dorothy C, 2019-04-23 Reviewed: Nathan, Vaishnavi, 2019-06-03 Reviewed: Hayward, Nicholas K, 2019-06-03 Edited: Orlic-Milacic, Marija, 2019-05-07 Evasion of Oxidative Stress Induced Senescence Due to Defective p16INK4A binding to CDK4 Missense mutations and small indels in the CDKN2A gene, which result in amino acid changes in p16INK4A that impair its ability to bind to CDK4, interfere with p16INK4A-mediated, oxidative stress-induced, cellular senescence (Chen 2000, Vurusaner et al. 2012).
Loss-of-function mutations in p16INK4A can also contribute to cancer by interfering with p16INK4A-mediated inhibition of NFKB signaling (Becker et al. 2005). Authored: Orlic-Milacic, Marija, 2018-12-24 Reviewed: Bennett, Dorothy C, 2019-04-23 Reviewed: Nathan, Vaishnavi, 2019-06-03 Reviewed: Hayward, Nicholas K, 2019-06-03 Edited: Orlic-Milacic, Marija, 2019-05-07 Reactome Database ID Release 77 9632697 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9632697 Reactome R-HSA-9632697 2 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9632697.2 22019631 Pubmed 2012 Tumor suppressor genes and ROS: complex networks of interactions Vurusaner, Beyza Poli, Giuseppe Basaga, Huveyda Free Radic. Biol. Med. 52:7-18 10911952 Pubmed 2000 Replicative senescence and oxidant-induced premature senescence. Beyond the control of cell cycle checkpoints Chen, Q M Ann. N. Y. Acad. Sci. 908:111-25 Evasion of Oxidative Stress Induced Senescence Due to Defective p16INK4A binding to CDK4 and CDK6 Missense and nonsense mutations in the CDKN2A gene that result in amino acid substitutions in p16INK4A or p16INK4A truncations, respectively, impairing its ability to bind to CDK4 and CDK6, interfere with p16INK4A-mediated induction of cellular senescence in response to oxidative stress (Chen 2000, Vurusaner et al. 2012).
Loss-of-function mutations in p16INK4A can also contribute to cancer by interfering with p16INK4A-mediated inhibition of NFKB signaling (Becker et al. 2005). Authored: Orlic-Milacic, Marija, 2018-12-24 Reviewed: Bennett, Dorothy C, 2019-04-23 Reviewed: Nathan, Vaishnavi, 2019-06-03 Reviewed: Hayward, Nicholas K, 2019-06-03 Edited: Orlic-Milacic, Marija, 2019-05-07 Reactome Database ID Release 77 9632700 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9632700 Reactome R-HSA-9632700 2 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9632700.2 Reactome Database ID Release 77 9632693 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9632693 Reactome R-HSA-9632693 3 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9632693.3 23190892 Pubmed 2013 Familial melanoma-associated mutations in p16 uncouple its tumor-suppressor functions Jenkins, Noah C Jung, Jae Liu, Tong Wilde, Megan Holmen, Sheri L Grossman, Douglas J. Invest. Dermatol. 133:1043-51 15377661 Pubmed 2004 Loss of proliferative capacity and induction of senescence in oxidatively stressed human fibroblasts Chen, Jian-Hua Stoeber, Kai Kingsbury, Sarah Ozanne, Susan E Williams, Gareth H Hales, C Nicholas J. Biol. Chem. 279:49439-46 27846439 Pubmed 2017 A new role for oxidative stress in aging: The accelerated aging phenotype in Sod1^-/- mice is correlated to increased cellular senescence Zhang, Yiqiang Unnikrishnan, Archana Deepa, Sathyaseelan S Liu, Yuhong Li, Y Ikeno, Yuji Sosnowska, Danuta Van Remmen, Holly Richardson, Arlan Redox Biol 11:30-37 20838381 Pubmed 2011 The p16(INK4A) tumor suppressor regulates cellular oxidative stress Jenkins, N C Liu, T Cassidy, P Leachman, S A Boucher, K M Goodson, A G Samadashwily, G Grossman, D Oncogene 30:265-74 10391689 Pubmed 1999 High incidence of allelic loss on chromosome 5 and inactivation of p15INK4B and p16INK4A tumor suppressor genes in oxystress-induced renal cell carcinoma of rats Tanaka, T Iwasa, Y Kondo, S Hiai, H Toyokuni, S Oncogene 18:3793-7 Evasion of Oxidative Stress Induced Senescence Due to p14ARF Defects One of the two main protein products of the CDKN2A gene, p14ARF (CDKN2A transcript 4, CDKN2A-4, ARF), contributes to oxidative stress induced cellular senescence by stabilizing TP53 (p53). The function of p14ARF in p53 stabilization through sequestration of MDM2, a p53 ubiquitin ligase, depends on the nuclear localization of p14ARF and its ability to interact with MDM2. The nuclear localization signal and the MDM2 interaction domain map to the first 15 amino acids of the N-terminus of p14ARF. This region is encoded by the p14ARF-specific exon 1beta of CDKN2A. An independent MDM2-binding domain is localized at the C-terminus of p14ARF (Lohrum et al. 2000). Insertion of 16 nucleotides in exon 1beta results in a frameshift truncation of p14ARF, responsible for a familial melanoma syndrome in which the p16INK4A product of the CDKN2A gene is unaffected. This mutation is rare and has so far been reported in one family only. The mutant protein, p14ARF R21RfsTER47 has the nucleotide localization signal and the N-terminal MDM2 interaction region preserved, but is unable to translocate from the cytosol to the nucleus, possibly due to aberrant conformation (Rizos, Puig et al. 2001), and also lacks the C-terminal MDM2 interaction region. Relocation of wild type p14ARF to the cytosol has been observed in melanoma (Rizos, Darmanian et al. 2001) and aggressive thyroid papillary carcinoma (Ferru et al. 2006). Genomic deletion of exon 1beta, with exons 1alpha, 2 and 3 intact, has been reported in about 30% of melanoma cases with genomic deletions involving the CDKN2A locus (Freedberg et al. 2008). Several different familial melanoma germline mutations map to the exon 1beta splice donor site (Harland et al. 2005).
The ability of p14ARF to localize to the nucleolus also plays a role in p14ARF-mediated stabilization of p53. Mutations in exon 2 of the CDKN2A gene can lead to missense mutations in p14ARF that affect its nucleolar localization and p53 stabilization, but the exact mechanism has not been fully elucidated (Zhang and Xiong 1999, reviewed by Fontana et al. 2019). Authored: Orlic-Milacic, Marija, 2019-06-28 综述:rizo,海伦,2019-07-08 Reviewed: Bennett, Dorothy C, 2019-08-12 Edited: Orlic-Milacic, Marija, 2019-07-16 Edited: Orlic-Milacic, Marija, 2019-08-14 Reactome Database ID Release 77 9646304 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9646304 Reactome R-HSA-9646304 2 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9646304.2 Reactome Database ID Release 77 9630747 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9630747 Reactome R-HSA-9630747 2 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9630747.2 28575665 Pubmed 2017 Senescence in Health and Disease He, Shenghui Sharpless, Norman E Cell 169:1000-1011 26646499 Pubmed 2015 Cellular senescence in aging and age-related disease: from mechanisms to therapy Childs, Bennett G Durik, Matej Baker, Darren J van Deursen, Jan M Nat. Med. 21:1424-35