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首页> 外文期刊>Cell cycle >TGFbeta1-induced activation of ATM and p53 mediates apoptosis in a Smad7-dependent manner.
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TGFbeta1-induced activation of ATM and p53 mediates apoptosis in a Smad7-dependent manner.

机译:TGFbeta1诱导的ATM和p53激活以Smad7依赖性方式介导凋亡。

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摘要

ATM, a DNA-damage sensitive kinase and p53, are frequently inactivated in a variety of cancers as they together with gammaH2AX are critical guardians against DNA damage. Here, we report of a functional cross-talk between the cytokine TGFbeta and p53, leading to apoptosis of epithelial cells, involving Smad7, a TGFbeta target gene p38 MAP kinase, and ATM. Using ectopic expression of p53, siRNA for Smad7, p38alpha-/- deficient cells and specific inhibitors, we show that TGF-beta induces apoptosis via ATM and p53 in epithelial cells. Intriguingly, Smad7 act as a scaffold protein to promote functional interactions between p38, ATM and p53 upon TGFbeta treatment, facilitating their activation. Smad7 colocalizes with gammaH2AX in DNA damage foci and was required for proper cell cycle checkpoints to prevent genetic instability. Our data imply that Smad7 plays a crucial role upstream of ATM and p53 to protect the genome from insults evoked by extracellular stress.
机译:ATM是一种对DNA损伤敏感的激酶和p53,在多种癌症中经常被灭活,因为它们与gammaH2AX一起是防止DNA损伤的关键守护者。在这里,我们报告细胞因子TGFbeta和p53之间的功能性串扰,导致上皮细胞凋亡,涉及Smad7,TGFbeta目标基因p38 MAP激酶和ATM。使用异位表达的p53,Smad7,p38alpha-/-缺陷细胞和特异性抑制剂的siRNA,我们证明TGF-β通过ATM和p53诱导上皮细胞凋亡。有趣的是,在TGFbeta处理后,Smad7充当支架蛋白来促进p38,ATM和p53之间的功能性相互作用,从而促进其激活。 Smad7与gammaH2AX在DNA损伤灶中共定位,并需要适当的细胞周期检查点来防止遗传不稳定性。我们的数据表明,Smad7在ATM和p53上游起着至关重要的作用,以保护基因组免受细胞外应激引起的侵害。

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