DNA 损伤/端粒应激诱导的衰老
中文名称
通路描述
由于致癌 RAS 诱导的线粒体功能障碍或环境压力，衰老细胞中活性氧（ROS）浓度增加，导致双链断裂（DSBs）（Yu and Anderson 1997）。此外，由致癌信号驱动的持续细胞分裂导致复制性耗竭，表现为端粒显著缩短（Harley et al. 1990, Hastie et al. 1990）。缩短的端粒无法结合保护性的 shelterin 复合物（Smogorzewska et al. 2000, de Lange 2005），并被识别为受损 DNA。进化上保守的 MRN 复合物（由 MRE11A、RAD50 和 NBN 亚基组成）结合 DSBs 和缩短的端粒（Wu et al. 2007）。一旦结合 DNA，MRN 复合物招募并激活 ATM 激酶（Lee and Paull 2005, Wu et al. 2007），导致 ATM 靶蛋白磷酸化，包括 TP53（p53）（Banin et al. 1998, Canman et al. 1998, Khanna et al. 1998）。磷酸化后的 TP53 在 serine S15 处结合 CDKN1A（也称为 p21、CIP1 或 WAF1）启动子并诱导 CDKN1A 转录（El-Deiry et al. 1993, Karlseder et al. 1999）。CDKN1A 抑制 CDK2 活性，导致 G1/S 细胞周期阻滞（Harper et al. 1993, El-Deiry et al. 1993）。SMURF2 在人类成纤维细胞端粒耗损时上调，并通过 RB1 和 TP53 诱导衰老表型，独立于其 TGF-β1 信号中的作用（Zhang and Cohen 2004）。SMURF2 参与的精确机制尚未阐明。
英文描述
Aryl hydrocarbon receptor signalling The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that belongs to the basic helix-loop-helix/PER-ARNT-SIM family of DNA binding proteins and controls the expression of a diverse set of genes. Two major types of environmental compounds can activate AHR signaling: halogenated aromatic hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and polycyclic aromatic hydrocarbons (PAH) such as benzo(a)pyrene. Unliganded AHR forms a complex in the cytosol with two copies of 90kD heat shock protein (HSP90AB1), one X-associated protein (AIP), and one p23 molecular chaperone protein (PTGES3). After ligand binding and activation, the AHR complex translocates to the nucleus, disassociates from the chaperone subunits, dimerises with the aryl hydrocarbon receptor nuclear translocator (ARNT) and transactivates target genes via binding to xenobiotic response elements (XREs) in their promoter regions. AHR targets genes of Phase I and Phase II metabolism, such as cytochrome P450 1A1 (CYP1A1), cytochorme P450 1B1 (CYP1B1), NAD(P)H:quinone oxidoreductase I (NQO1) and aldehyde dehydrogenase 3 (ALHD3A1). This is thought to be an organism's response to foreign chemical exposure and normally, foreign chemicals are made less reactive by the induction and therefore increased activity of these enzymes (Beischlag et al. 2008).
AHR itself is regulated by the aryl hydrocarbon receptor repressor (AHRR, aka BHLHE77, KIAA1234), an evolutionarily conserved bHLH-PAS protein that inhibits both xenobiotic-induced and constitutively active AHR transcriptional activity in many species. AHRR resides predominantly in the nuclear compartment where it competes with AHR for binding to ARNT. As a result, there is competition between AHR:ARNT and AHRR:ARNT complexes for binding to XREs in target genes and AHRR can repress the transcription activity of AHR (Hahn et al. 2009, Haarmann-Stemmann & Abel 2006).
AHR itself is regulated by the aryl hydrocarbon receptor repressor (AHRR, aka BHLHE77, KIAA1234), an evolutionarily conserved bHLH-PAS protein that inhibits both xenobiotic-induced and constitutively active AHR transcriptional activity in many species. AHRR resides predominantly in the nuclear compartment where it competes with AHR for binding to ARNT. As a result, there is competition between AHR:ARNT and AHRR:ARNT complexes for binding to XREs in target genes and AHRR can repress the transcription activity of AHR (Hahn et al. 2009, Haarmann-Stemmann & Abel 2006).
所含基因
7 个基因