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The role of GTSE1 in G2/M progression after G2 checkpoint

Reactome ID: R-HSA-8852276

中文名称

胶原纤维交联

通路描述

去除 N 端和 C 端前肽后，纤维状胶原分子聚集形成微纤维状阵列，并由共价分子间交联稳定。这些交联依赖于酪氨酸氧化酶（LOX）对前肽区特定赖氨酸或羟赖氨酸的氧化脱氨作用，随后自发形成共价分子间交联（Pinnell & Martin 1968, Siegel et al. 1970, 1974, Maki 2009, Nishioka et al. 2012）。羟赖氨酸由羟赖氨酸酶（LH）在细胞内形成。存在不同的 LH 负责螺旋和前肽赖氨酸的羟化（Royce & Barnes 1985, Knott et al.1997, Takaluoma et al. 2007, Myllyla 2007）。形成的交联化学性质取决于前肽中是否含有赖氨酸或羟赖氨酸（Barnes et al. 1974），这取决于羟赖氨酸在翻译后由 LH 将胶原赖氨酸的比例。赖氨酸途径在成人皮肤、角膜和巩膜中占主导地位，而羟赖氨酸途径主要发生在骨、软骨、韧带、肌腱、胚胎皮肤和大多数结缔组织中（Eyre 1987, Eyre & Wu 2005, Eyre et al. 2008）。LOX 氧化赖氨酸或羟赖氨酸残基产生烯丙醛和羟烯丙醛醛。这些醛可以自发与其他醛反应形成醛醇缩合产物（内部分子间交联），或与未修饰的赖氨酸或羟赖氨酸残基反应形成分子间交联。交联途径主要由前肽和三级结构赖氨酸残基的羟化模式调节。当酪氨酸氧化酶产生的醛来自赖氨酸残基时，烯丙醛交联途径导致形成醛胺交联（Eyre & Wu 2005）。这些在生理条件下稳定，但在酸性 pH 或升高温度下易被裂解。当羟赖氨酸残基是醛的来源时，羟烯丙醛交联途径导致形成更稳定的酮胺交联。前肽赖氨酸残基可由 LOX 转化为烯丙醛，可与螺旋羟赖氨酸残基形成赖氨酸醛醛胺交联脱氢羟赖丝诺赖氨酸（deHHLNL）（Bailey & Peach 1968, Eyre et al. 2008）。如果前肽残基是羟赖氨酸，LOX 产生的羟烯丙醛可与螺旋羟赖氨酸残基形成 Schiff 基，随后自发发生 Amadori 重排，形成酮胺交联羟赖丝诺 5-酮赖氨酸（HLKNL）。这种稳定的交联在前肽残基主要被羟化的组织中形成，如胎儿骨和软骨，解释了这些组织胶原蛋白的相对不溶性（Bailey et al. 1998）。在骨中，前肽羟烯丙醛可与螺旋赖氨酸的 ε-氨基反应，形成的 Schiff 基随后发生 Amadori 重排形成赖氨酸 - 羟赖丝诺赖氨酸（LHNL）。在软骨中，酮胺交联的成熟机制已被报道，导致形成角利尼（Eyre et al. 2010）。这些二价交联随着结缔组织的成熟而大大减少，这是由于与相邻肽体的进一步自发反应（Bailey & Shimokomaki 1971, Robins & Bailey 1973）形成的三价和四价交联。在成熟组织中，胶原蛋白交联主要是三价的。最常见的包括吡啶啉或 3-羟基吡啉交联，即羟赖丝 - 吡啉（HL-Pyr）和赖丝 - 吡啉（L-Pyr）交联（Eyre 1987, Ogawa et al. 1982, Fujimoto et al. 1978）。HL-Pyr 由三个羟赖氨酸残基形成，HLKNL 加上额外的羟烯丙醛。它主要存在于高度羟化的胶原中，如软骨中的 II 型胶原。L-Pyr 由两个羟赖氨酸和一个赖氨酸形成，LKNL 加上额外的羟烯丙醛，主要在钙化组织中（Bailey et al. 1998）。三价胶原蛋白交联还可以形成吡咯，即赖丝 - 吡咯（L-Pyrrole）或羟赖丝 - 吡咯（HL-Pyrrole），分别由 LKNL 或 HLKNL 与烯丙醛反应形成（Scott et al. 1981, Kuypers et al. 1992）。当 DeH-HLNL 与组氨酸反应形成组氨酸 - 羟赖丝诺赖氨酸（HHL）时，可形成三价交联，存在于皮肤和角膜（Yamauchi et al. 1987, 1996）。这可以与额外的赖氨酸反应形成四价交联组氨酸 - 羟赖丝诺德索明素（Reiser et al. 1992, Yamauchi et al. 1996）。胶原蛋白 IV 网络的交联还可能涉及硫胺亚胺键（Vanacore et al. 2009），由过氧化物酶催化，该酶存在于基底膜（Bhave 2012）。为了清晰起见，此处仅表示胶原 I 的链间交联。虽然每种交联的形成在这里都表示为独立事件，但由于每种交联的形成是部分和随机的，且赖氨酸羟化及随后的酪氨酸氧化是随机的，因此同一胶原纤维内任何这些交联事件的组合都可能发生。
英文描述
The role of GTSE1 in G2/M progression after G2 checkpoint GTSE1 (B99) was identified as a microtubule-associated protein product of the mouse B99 gene, which exhibits both a cell cycle regulated expression, with highest levels in G2, and DNA damage triggered expression under direct control of TP53 (p53) (Utrera et al. 1998, Collavin et al. 2000). Human GTSE1, similar to the mouse counterpart, binds to microtubules, shows cell cycle regulated expression with a peak in G2 and plays a role in G2 checkpoint recovery after DNA damage but is not transcriptionally regulated by TP53 (Monte et al. 2003, Monte et al. 2004, Scolz et al. 2012).In G1 cells, GTSE1 is found at the microtubule lattice, likely due to direct binding to tubulin. An evolutionarily conserved interaction between GTSE1 and MAPRE1 (EB1), a microtubule plus end protein, promotes GTSE1 localization to the growing tip of the microtubules, which contributes to cell migration and is likely involved in cancer cell invasiveness. Highly invasive breast cancer cell lines exhibit high GTSE1 levels in G1, while GTSE1 levels in G1 are normally low. At the beginning of mitotic prometaphase, GTSE1 is phosphorylated by mitotic kinase(s), possibly CDK1, in proximity to the MAPRE1-binding region, causing GTSE1 dissociation from the plus end microtubule ends (Scolz et al. 2012).During G2 checkpoint recovery (cell cycle re-entry after DNA damage induced G2 arrest), GTSE1 relocates to the nucleus where it binds TP53 and, in an MDM2-dependent manner, promotes TP53 cytoplasmic translocation and proteasome mediated degradation (Monte et al. 2003, Monte et al. 2004). Relocation of GTSE1 to the nucleus in G2 phase depends on PLK1-mediated phosphorylation of GTSE1 (Liu et al. 2010).GTSE1-facilitated down-regulation of TP53 in G2 allows cells to avoid TP53 mediated apoptosis upon DNA damage and to re-enter cell cycle (Monte et al. 2003). While TP53 down-regulation mediated by GTSE1 in G2 correlates with decreased expression of TP53 target genes involved in apoptosis and cell cycle arrest, GTSE1 can also increase the half-life of the TP53 target p21 (CDKN1A). GTSE1-mediated stabilization of CDKN1A involves interaction of GTSE1 with CDKN1A and its chaperone complex, consisting of HSP90 and FKBPL (WISp39), and may be involved in resistance to paclitaxel treatment (Bublik et al. 2010).

所含基因

64 个基因
ADRM1 CCNB1 CCNB2 CDK1 CDKN1A FKBPL GTSE1 HSP90AA1 HSP90AB1 MAPRE1 PLK1 PSMA1 PSMA2 PSMA3 PSMA4 PSMA5 PSMA6 PSMA7 PSMB1 PSMB2 PSMB3 PSMB4 PSMB5 PSMB6 PSMB7 PSMC1 PSMC2 PSMC3 PSMC4 PSMC5 PSMC6 PSMD1 PSMD11 PSMD12 PSMD13 PSMD14 PSMD2 PSMD3 PSMD6 PSMD7 PSMD8 RPS27A SEM1 TUBA1A TUBA1B TUBA1C TUBA3C TUBA3D TUBA3E TUBA4A TUBA4B TUBA8 TUBAL3 TUBB1 TUBB2A TUBB2B TUBB3 TUBB4A TUBB4B TUBB6 TUBB8 UBA52 UBB UBC