Department of Biological Sciences, Faculty of Science, National University of Singapore, 14 Science Drive 4, Singapore 117543, Singapore.
Int J Biochem Cell Biol. 2011 Apr;43(4):535-44. doi: 10.1016/j.biocel.2010.12.009. Epub 2010 Dec 14.
DNA damage stabilizes and activates p53, which selectively induces downstream targets to modulate the cellular response. As a homeostatic regulator of cell cycle checkpoint, the p53 target Wip1 plays essential roles in releasing cells from DNA damage-induced checkpoints after appropriate repair of the damaged-DNA. It is unknown how Wip1 performs when the DNA damage is beyond repair. Here we address that Wip1 displays dose-dependent responses to UVC irradiation. A low dose of UVC, which stimulates intra-S phase cell cycle arrest, transiently induces the Wip1 protein levels in a p53-dependent manner. In contrast, a high dose of UVC, which induces apoptosis, suppresses the Wip1 protein levels in a p53-independent manner. The UVC dose-dependent response of Wip1 correlates not only with the cellular response but also with the activity of p53. Wip1 dephosphorylates p53 on its Ser15 residue. However, the mutual regulation between Wip1 and p53 is only triggered by a low dose of UVC. In response to a high dose of UVC, the sustained activation of p53 fails to induce the downstream targets, including Wip1, Mdm2, p21 and GADD45α. Nonetheless, the reduced Wip1 level contributes to the sustained accumulation of phospho-p53 (Ser15) in response to a high dose of UVC. Our results suggest that Wip1 is regulated by UVC in a dose-dependent manner. Moreover, the mutual regulation between Wip1 and p53 is highly dose-dependent upon UVC irradiation, and this contributes to the different outcomes of the cellular response to UVC.
DNA 损伤稳定并激活 p53，p53 选择性地诱导下游靶标来调节细胞反应。作为细胞周期检查点的内稳态调节剂，p53 靶标 Wip1 在受损 DNA 适当修复后，从 DNA 损伤诱导的检查点释放细胞方面发挥着重要作用。目前尚不清楚在 DNA 损伤无法修复的情况下 Wip1 如何发挥作用。在这里，我们研究了 Wip1 对 UVC 照射的剂量依赖性反应。低剂量的 UVC 会刺激细胞在 S 期内停滞，会以 p53 依赖的方式短暂诱导 Wip1 蛋白水平升高。相比之下，高剂量的 UVC 会诱导细胞凋亡，以 p53 非依赖的方式抑制 Wip1 蛋白水平。Wip1 对 UVC 的剂量依赖性反应不仅与细胞反应相关，还与 p53 的活性相关。Wip1 使 p53 的 Ser15 残基去磷酸化。然而，Wip1 和 p53 之间的相互调节仅由低剂量的 UVC 触发。对于高剂量的 UVC，p53 的持续激活无法诱导下游靶标，包括 Wip1、Mdm2、p21 和 GADD45α。尽管如此，Wip1 水平的降低有助于在高剂量 UVC 下持续积累磷酸化 p53（Ser15）。我们的结果表明，Wip1 受到 UVC 的剂量依赖性调节。此外，Wip1 和 p53 之间的相互调节在受到 UVC 照射时高度依赖于剂量，这有助于解释细胞对 UVC 反应的不同结果。
