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Mechanisms underlying the pro-survival pathway of p53 in suppressing mitotic death induced by adriamycin

机译:p53抑制亚霉素诱导的有丝分裂死亡的P53潜水途径的机制

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The p53 tumor suppressor responds to chemotherapeutic stress by triggering apoptosis or eliciting pro-survival pathway through arresting cell cycle progression for DNA damage repair. Here we examined the pro-survival activity of p53 on the adriamycin-induced stress using H1299 cells stably expressing tsp53(V143A), a temperature-sensitive mutant activating only the subset of p53 target genes related to growth arrest and DNA repair, but not apoptosis. At 38 degrees C, cells evaded from adriamycin-induced G2 arrest and died of apoptosis and mitotic catastrophe, which could be inhibited by Cdk inhibitors. Activation of functional tsp53(V143A) at 32 degrees C led to suppression of Cdk1/2 activities and Cyclin B1/Cdk1 expression, cells exhibited prolonged G2 arrest, regained reproductive potential and were protected from mitotic catastrophe induced by adriamycin. Inhibition of mitotic catastrophe and Cyclin B1/Cdk1 expression was ablated upon silencing p21(Waf1) expression in tsp53(V143A)-H1299 cells or in HCT116 cells. Together we show that p21(Waf1) is a key component of G2 checkpoint necessary and sufficient for protecting tumor cells against adriamycin-induced mitotic catastrophe. (C) 2007 Elsevier Inc. All rights reserved.
机译:P53肿瘤抑制剂通过通过阻止细胞周期进展来触发细胞凋亡或引发的促募集性途径来响应化学治疗应力。在这里,我们使用H1299细胞稳定地表达TSP53(V143A)的H1299细胞检查P53对亚霉素诱导的应力的P53,仅激活P53靶基因的子集与生长停滞和DNA修复,但不具有细胞凋亡。在38℃下,细胞从Adriamycin诱导的G2抑制和死于细胞凋亡和有丝分裂灾难,这可能被CDK抑制剂抑制。在32℃下激活功能性TSP53(V143A)导致CDK1 / 2活性的抑制和细胞周期蛋白B1 / CDK1表达,细胞延长了G2抑制,恢复生殖潜力,并受到阿霉素诱导的有丝分裂灾难的影响。在TSP53(V143A)-H1299细胞中的沉默P21(WAF1)表达或HCT116细胞中,将抑制有丝分裂灾难和细胞周期蛋白B1 / CDK1表达的表达被烧成。我们一起表明P21(WAF1)是G2检查点所必需的关键组分,并且足以保护肿瘤细胞免受腺苷诱导的有丝分裂灾害的影响。 (c)2007年elestvier Inc.保留所有权利。

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