bioax途径由Reactome数据库中的“p-Bmal1:p-Clock,Npas2结合Nr1d1基因”转化而来。 p-Bmal1:p-Clock,Npas2结合Nr1d1基因

p-Bmal1:p-Clock,Npas2结合Nr1d1基因

Bmal1:Clock (Arntl:Clock)和Bmal1:Npas2 (Arntl:Npas2)异源二聚体结合目的基因启动子中的E-box元件(consensus CACGTG)。两个间隔6bp的E-box元件足以确定报告基因的昼夜转录。Rev-erba (Nr1d1)启动子有一个E-box，受Bmal1:Clock调控。Bmal1:Npas2的调控也被证明了，这导致了时钟和Npas2至少部分冗余的结论。

作者:May, Bruce, 2015-01-14 评论:Albrecht, Urs, 2010-06-23 评论:Delaunay, F, 2010-06-23 评论:Hirota, T, 2010-06-23 引用本文:Kay, SA, 2010-06-23 编辑本文:May, Bruce, 2015-01-14

Reactome DB_ID: 5663171

核浆去 0005654

运用:ENSMUSG00000020889 Nr1d1 Nr1d1 Reactome //www.joaskin.com 亩骶

NCBI分类法 10090 运用 ENSMUSG00000020889

Reactome DB_ID: 508608

p-Bmal1: p-Clock Npas2(核浆)

p-Bmal1: p-Clock Npas2

p-Arntl: p-Clock Npas2异质二聚体

Reactome DB_ID: 508690

UniProt: Q9WTL8 Arntl

Arntl

Arntl Bmal1 功能转录激活因子，构成生物钟的核心成分。生物钟是一个内部的计时系统，通过基因表达产生大约24小时的生物钟节律来调节各种生理过程，这些节律转化为代谢和行为的节律。它源于拉丁语词根“circa”（约）和“diem”（日），是多种生理功能的重要调节者，包括新陈代谢、睡眠、体温、血压、内分泌、免疫、心血管和肾功能。由两个主要组成部分组成：位于大脑视交叉上核（SCN）的中央时钟和几乎存在于每个组织和器官系统的外围时钟。中央和外围时钟都可以通过环境提示重置，也称为Zeitgebers（德语中的“计时器”）。中央时钟的主要时脉是光，由视网膜感知并直接向SCN发送信号。中央时钟通过神经元和激素信号、体温和与进食相关的线索，使所有时钟与外部光/暗周期保持一致，从而进入外围时钟。昼夜节律允许生物体通过调节基因表达，每24小时产生一次蛋白质表达峰值，以控制特定生理过程在太阳日最活跃的时间，从而在分子水平上实现与其环境的时间内稳态。核心时钟成分（时钟、NPAS2、ARNTL/BMAL1、ARNTL2/BMAL2、PER1、PER2、PER3、CRY1和CRY2）的转录和翻译在节律生成中起着关键作用，而翻译后修饰（PTM）造成的延迟对于确定节律的周期（tau）很重要（tau指一个节律的周期，是一个完整周期的时间长度）.昼夜节律与昼夜周期同步，而超昼夜节律和超昼夜节律的周期分别短于24小时和长于24小时。昼夜节律的破坏有助于心血管疾病、癌症、代谢综合征和衰老的病理学。转录/翻译反馈环（TTFL）形成分子昼夜节律时钟机制的核心。转录因子，clock或NPAS2和ARNTL/BMAL1或ARNTL2/BMAL2，形成反馈环的正支，以异二聚体的形式发挥作用，并激活核心时钟基因和时钟控制基因（参与关键代谢过程）的转录，装有电子箱元件（5’-CACGTG-3’）核心时钟基因：PER1/2/3和CRY1/2，它们是转录抑制因子，形成反馈环的负分支，并与时钟| NPAS2-ARNTL/BMAL1 | ARNTL2/BMAL2异二聚体相互作用，抑制其活性，从而对自身的表达进行负调控。这种异二聚体还激活核受体NR1D1/2和RORA/B/G，形成第二个反馈环，分别激活和抑制ARNTL/BMAL1转录。ARNTL/BMAL1通过规范Wnt信号通路基因的转录控制，积极调节肌生成，消极调节脂肪生成。在正常胰腺β细胞功能中发挥作用；通过调节抗氧化基因NFE2L2/NRF2及其靶点SESN2、PRDX3、CCLC和CCLM来调节葡萄糖刺激的胰岛素分泌。负调节mTORC1信号通路；调节MTOR和DEPTOR的表达。控制Ly6C炎性单核细胞的昼夜振荡；PRC2复合物的节律性募集调节卵巢中HSD3B2、STAR、PTGS2、CYP11A1、CYP19A1和LHCGR的表达，以及参与毛发生长的基因。通过调节神经干/祖细胞的及时进入，在成年海马神经发生中发挥重要作用（NSPCs）进入细胞周期和细胞周期退出前发生的细胞分裂数量。调节CIART和KLF11的昼夜节律表达。CLOCK-ARNTL/BMAL1异二聚体调节SERPINE1/PAI1、VWF、B3、CCRN4L/NOC、NAMPT、DBP、MYOD1、PPARGC1A、PPARGC1B、SIRT1、GYS2、F7、NGFR、GNRHR、BHLHE40/DEC1、ATF4、M的昼夜节律表达TA1、KLF10以及与葡萄糖和脂质代谢有关的基因。促进有节奏的染色质开放，调节其他转录因子的DNA可及性。可能在精子发生中发挥作用；有助于染色质体组装和生理学。NPAS2-ARNTL/BMAL1异二聚体正性调节MAOA、F7的表达和LDHA，并通过调节视网膜中腺苷酸环化酶1型（ADCY1）的节律性表达来调节日间对比敏感度的昼夜节律。CLOCK-ARNTL/BMAL1异二聚体的首选结合基序为5'-CACGTGA-3'，其包含侧翼Ala residue in addition to the canonical 6-nucleotide E-box sequence (By similarity). CLOCK specifically binds to the half-site 5'-CAC-3', while ARNTL binds to the half-site 5'-GTGA-3' (By similarity). The CLOCK-ARNTL/BMAL1 heterodimer also recognizes the non-canonical E-box motifs 5'-AACGTGA-3' and 5'-CATGTGA-3' (By similarity). Essential for the rhythmic interaction of CLOCK with ASS1 and plays a critical role in positively regulating CLOCK-mediated acetylation of ASS1 (PubMed:28985504). Plays a role in protecting against lethal sepsis by limiting the expression of immune checkpoint protein CD274 in macrophages in a PKM2-dependent manner (PubMed:29996098). Regulates the diurnal rhythms of skeletal muscle metabolism via transcriptional activation of genes promoting triglyceride synthesis (DGAT2) and metabolic efficiency (COQ10B) (PubMed:30096135).ACTIVITY REGULATION The redox state of the cell can modulate the transcriptional activity of the CLOCK-ARNTL/BMAL1 and NPAS2-ARNTL/BMAL1 heterodimers; NADH and NADPH enhance the DNA-binding activity of the heterodimers.SUBUNIT Component of the circadian clock oscillator which includes the CRY1/2 proteins, CLOCK or NPAS2, ARNTL/BMAL1 or ARNTL2/BMAL2, CSNK1D and/or CSNK1E, TIMELESS and the PER1/2/3 proteins (PubMed:11779462). Forms a heterodimer with CLOCK (PubMed:9616112, PubMed:16717091, PubMed:16980631, PubMed:18662546, PubMed:19946213, PubMed:19330005, PubMed:21613214, PubMed:23970558, PubMed:22653727). The CLOCK-ARNTL/BMAL1 heterodimer is required for E-box-dependent transactivation, for CLOCK nuclear translocation and degradation, and, for phosphorylation of both CLOCK and ARNTL/BMAL1 (PubMed:11779462). Part of a nuclear complex which also includes RACK1 and PRKCA; RACK1 and PRKCA are recruited to the complex in a circadian manner (PubMed:20093473). Interacts with NPAS2 (PubMed:16628007). Interacts with EZH2 (PubMed:16717091, PubMed:23970558). Interacts with SUMO3 (PubMed:18644859). Interacts with SIRT1 (PubMed:18662546, PubMed:18662547, PubMed:19299583). Interacts with AHR (PubMed:20106950). Interacts with ID1, ID2 and ID3 (PubMed:20861012). Interacts with DDX4 (PubMed:22900038). Interacts with OGT (PubMed:23337503). Interacts with EED and SUZ12 (PubMed:23970558). Interacts with MTA1 (PubMed:24089055). Interacts with CIART (PubMed:24385426, PubMed:24736997). Interacts with HSP90 (By similarity). Interacts with KAT2B and EP300 (By similarity). Interacts with BHLHE40/DEC1 and BHLHE41/DEC2 (PubMed:12397359). Interacts with RELB and the interaction is enhanced in the presence of CLOCK (PubMed:22894897). Interacts with PER1, PER2, CRY1 and CRY2 and this interaction requires a translocation to the nucleus (PubMed:18430226, PubMed:19605937, PubMed:20840750, PubMed:21613214, PubMed:24154698). Interaction of the CLOCK-ARNTL/BMAL1 heterodimer with PER or CRY inhibits transcription activation (PubMed:21613214). Interaction of the CLOCK-ARNTL/BMAL1 with CRY1 is independent of DNA but with PER2 is off DNA (PubMed:21613214). The CLOCK-ARNTL/BMAL1 heterodimer interacts with GSK3B (PubMed:19946213, PubMed:20049328). Interacts with KDM5A (PubMed:21960634). Interacts with KMT2A; in a circadian manner (PubMed:21113167). Interacts with UBE3A (By similarity). Interacts with PRKCG (PubMed:23185022). Interacts with MAGEL2 (PubMed:22208286). Interacts with NCOA2 (PubMed:24529706). Interacts with THRAP3 (PubMed:24043798). The CLOCK-ARNTL/BMAL1 heterodimer interacts with PASD1 (By similarity). Interacts with PASD1 (By similarity). Interacts with USP9X (PubMed:29626158). Interacts with PIWIL2 (via PIWI domain) (PubMed:28903391). Interacts with HDAC3 (PubMed:26776516). Interacts with HNF4A (By similarity).TISSUE SPECIFICITY Expressed in liver and testis (at protein level). Expressed in the suprachiasmatic nucleus (SCN) in a circadian manner (PubMed:29138967).INDUCTION Expressed in a circadian manner in the liver.PTM Ubiquitinated, leading to its proteasomal degradation (PubMed:16980631, PubMed:18644859, PubMed:23185022, PubMed:26776516). Deubiquitinated by USP9X (PubMed:29626158).PTM O-glycosylated; contains O-GlcNAc. O-glycosylation by OGT prevents protein degradation by inhibiting ubiquitination. It also stabilizes the CLOCK-ARNTL/BMAL1 heterodimer thereby increasing CLOCK-ARNTL/BMAL1-mediated transcription of genes in the negative loop of the circadian clock such as PER1/2/3 and CRY1/2.PTM Acetylated on Lys-544 upon dimerization with CLOCK. Acetylation facilitates CRY1-mediated repression. Deacetylated by SIRT1, which may result in decreased protein stability.PTM Phosphorylated upon dimerization with CLOCK. Phosphorylation enhances the transcriptional activity, alters the subcellular localization and decreases the stability of the CLOCK-ARNTL/BMAL1 heterodimer by promoting its degradation. Phosphorylation shows circadian variations in the liver with a peak between CT10 to CT14. Phosphorylation at Ser-97 by CK2 is essential for its nuclear localization, its interaction with CLOCK and controls CLOCK nuclear entry. Dephosphorylation at Ser-85 is important for dimerization with CLOCK and transcriptional activity (By similarity).PTM Sumoylated on Lys-266 upon dimerization with CLOCK. Predominantly conjugated to poly-SUMO2/3 rather than SUMO1 and the level of these conjugates undergo rhythmic variation, peaking at CT9-CT12. Sumoylation localizes it exclusively to the PML body and promotes its ubiquitination in the PML body, ubiquitin-dependent proteasomal degradation and the transcriptional activity of the CLOCK-ARNTL/BMAL1 heterodimer.PTM Undergoes lysosome-mediated degradation in a time-dependent manner in the liver.DISRUPTION PHENOTYPE Mice are characterized by reduced lifespan, and the presence of a number of pathologies characteristic of pre-mature aging and increased oxidative stress. They show impaired functional connectivity, increased oxidative damage and severe astrogliosis in the brain. They also exhibit accelerated thrombosis with elevated levels of thrombogenic factors, including VWF, SERPINE1/PAI1, and fibrinogen. Both male and female mice are infertile and male mice have low testosterone and high luteinizing hormone serum levels and a significant decrease in sperm count (PubMed:18258755, PubMed:22101268, PubMed:24270424, PubMed:24481314). Conditional knockout in myeloid cells increases the risk of sepsis lethality which is associated with elevated lactate production and CD274 expression in macrophages (PubMed:29996098). Myeloid-cell-specific ARNTL/BMAL1 and PKM2 double knockout reduces the risk of sepsis lethality which is associated with reduced serum lactate levels and reduced CD274 expression in macrophages (PubMed:29996098). Conditional knockout in skeletal muscle leads to impaired skeletal muscle triglyceride biosynthesis, accumulation of bioactive lipids and amino acids and reduced mitochondrial efficiency (PubMed:30096135). UniProt Q9WTL8

o-磷酸- l -丝氨酸位置未知 O-phospho-L-serine (MOD: 00046)

链坐标

平等的

632

平等的

从Reactome中的EntitySet转换而来

Reactome DB_ID: 508674

p-Clock, p-Npas2(核浆) 从Reactome中的EntitySet转换而来。每个同义词是一个PhysicalEntity的名称，每个XREF指向一个PhysicalEntity p-Npas2(核浆) p-S-Clock(核浆) UniProt P97460 UniProt O08785 Reactome数据库ID Release 77 508608 数据库标识符。使用此URL连接到Reactome中的此实例的网页://www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=508608 Reactome r - mmu - 508608

Reactome稳定的标识符。使用此URL连接到Reactome中的此实例的网页://www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-508608.1

Reactome DB_ID: 5663190

p-Bmal1: p-Clock Npas2: Nr1d1基因(核浆)

p-Bmal1: p-Clock Npas2: Nr1d1基因

Reactome DB_ID: 5663171

Reactome DB_ID: 508608

Reactome数据库ID Release 77 5663190 数据库标识符。使用此URL连接到Reactome中的此实例的网页://www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=5663190 Reactome r - mmu - 5663190

Reactome稳定的标识符。使用此URL连接到Reactome中的此实例的网页://www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5663190.1 Reactome数据库ID Release 77 5663147 数据库标识符。使用此URL连接到Reactome中的此实例的网页://www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=5663147 Reactome r - mmu - 5663147

Reactome稳定的标识符。使用此URL连接到Reactome中的此实例的网页://www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5663147.1 17417633 Pubmed 2007 在视交叉上生物钟中，CLOCK和NPAS2有重叠的作用 DeBruyne,摩根大通韦弗,博士雷佩特,SM Nat > 10:543-5 15591021 Pubmed 2004 孤儿受体Rev-erbalpha基因是昼夜节律起搏器的靶点 Triqueneaux G Thenot,年代 Kakizawa T Antoch,议员萨菲R 高桥,JS 德劳内F Laudet V J Mol Endocrinol 33:585-608 12150932 Pubmed 2002 孤儿核受体REV-ERBalpha控制哺乳动物昼夜节律振荡器阳性肢体内的昼夜转录 Preitner N Damiola F Lopez-Molina L Zakany J Duboule D 阿尔布雷特,用户需求说明书 Schibler U 细胞110:251-60