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首页> 外文期刊>Molecular and Cellular Biology >Glycogen synthase kinase 3 beta phosphorylates p21(WAF1/CIP1) for proteasomal degradation after UV irradiation
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Glycogen synthase kinase 3 beta phosphorylates p21(WAF1/CIP1) for proteasomal degradation after UV irradiation

机译：糖原合酶激酶 3 β 磷酸化 p21（WAF1/CIP1） 用于紫外线照射后蛋白酶体降解

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摘要

UV irradiation has been reported to induce p21(WAF1/CIP1) protein degradation through a ubiquitin-proteasome pathway, but the underlying biochemical mechanism remains to be elucidated. Here, we show that ser-114 phosphorylation of p21 protein by glycogen synthase kinase 3 beta (GSK-3 beta) is required for its degradation in response to UV irradiation and that GSK-3 beta activation is a downstream event in the ATR signaling pathway triggered by UV. UV transiently increased GSK-3 beta activity, and this increase could be blocked by caffeine or by ATR small interfering RNA, indicating ATR-dependent activation of GSK-3 beta. ser-114, located within the putative GSK-3 beta target sequence, was phosphorylated by GSK-3 beta upon UV exposure. The nonphosphorylatable S114A mutant of p21 was protected from UV-induced destabilization. Degradation of p21 protein by UV irradiation was independent of p53 status and prevented by proteasome inhibitors. In contrast to the previous report, the proteasomal degradation of p21 appeared to be ubiquitination independent. These data show that GSK-3 beta is activated by UV irradiation through the ATR signaling pathway and phosphorylates p21 at ser-114 for its degradation by the proteasome. To our knowledge, this is the first demonstration of GSK-3 beta as the missing link between UV-induced ATR activation and p21 degradation.
机译：据报道，紫外线照射通过泛素-蛋白酶体途径诱导 p21（WAF1/CIP1） 蛋白降解，但潜在的生化机制仍有待阐明。在这里，我们表明糖原合酶激酶 3 β （GSK-3 β） 对 p21 蛋白的 ser-114 磷酸化是其响应紫外线照射降解所必需的，并且 GSK-3 β 激活是 ATR 信号通路中的下游事件由紫外线触发。紫外线瞬时增加 GSK-3 β 活性，这种增加可能被咖啡因或 ATR 小干扰 RNA 阻断，表明 GSK-3 β 的 ATR 依赖性激活。ser-114 位于推定的 GSK-3 β 靶序列内，在紫外线照射下被 GSK-3 β 磷酸化。p21 的非磷酸化 S114A 突变体受到保护，免受紫外线诱导的不稳定。紫外线照射下 p21 蛋白的降解与 p53 状态无关，并由蛋白酶体抑制剂阻止。与之前的报告相比，p21的蛋白酶体降解似乎与泛素化无关。这些数据表明，GSK-3 β 通过 ATR 信号通路被紫外线照射激活，并在 ser-114 位点磷酸化 p21，使其被蛋白酶体降解。据我们所知，这是 GSK-3 β 作为紫外诱导的 ATR 激活和 p21 降解之间缺失环节的首次证明。

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