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p53 Down-Regulates CHK1 through p21 and the Retinoblastoma Protein

机译：p53通过p21和视网膜母细胞瘤蛋白下调CHK1

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Both fission yeast and mammalian cells require the function of the checkpoint kinase CHK1 for G2 arrest after DNA damage. The tumor suppressor p53, a well-studied stress response factor, has also been shown to play a role in DNA damage G2 arrest, although in a manner that is probably independent of CHK1. p53, however, can be phosphorylated and regulated by both CHK1 as well as another checkpoint kinase, hCds1 (also called CHK2). It was therefore of interest to determine whether reciprocally, p53 affects either CHK1 or CHK2. We found that induction of p53 either by diverse stress signals or ectopically using a tetracycline-regulated promoter causes a marked reduction in CHK1 protein levels. CHK1 downregulation by p53 occurs as a result of reduced CHK1 RNA accumulation, indicating that repression occurs at the level of transcription. Repression of CHK1 by p53 requires p21, since p21 alone is sufficient for this to occur and cells lacking p21 cannot downregulate CHK1. Interestingly, pRB is also required for CHK1 downregulation, suggesting the possible involvement of E2F-dependent transcription in the regulation of CHK1. Our results identify a new repression target of p53 and suggest that p53 and CHK1 play interdependent and complementary roles in regulating both the arrest and resumption of G2 after DNA damage.
机译：裂变酵母和哺乳动物细胞都需要检查点激酶CHK1的功能来破坏DNA损伤后的G 2 。研究表明，抑癌基因p53是一种经过充分研究的应激反应因子，尽管它可能独立于CHK1，但在DNA损伤G 2 停滞中也发挥了作用。然而，p53可以被CHK1以及另一种检查点激酶hCds1（也称为CHK2）磷酸化和调节。因此，有必要确定p53是否反过来影响CHK1或CHK2。我们发现，通过多种应激信号或使用四环素调节的启动子异位诱导p53会导致CHK1蛋白水平显着降低。 p53导致CHK1下调是CHK1 RNA积累减少的结果，这表明阻遏作用发生在转录水平。通过p53抑制CHK1需要p21，因为仅p21足以使其发生并且缺乏p21的细胞不能下调CHK1。有趣的是，CHB1的下调也需要pRB，这表明E2F依赖性转录可能参与CHK1的调节。我们的结果确定了p53的新的抑制目标，并建议p53和CHK1在调节DNA损伤后G 2 的阻滞和恢复中起相互依赖和互补的作用。

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