Glycogen Synthase Kinase 3 (cid:2) Phosphorylates p21 WAF1/CIP1 for Proteasomal Degradation after UV Irradiation (cid:1) †
Glycogen Synthase Kinase 3 (cid:2) Phosphorylates p21 WAF1/CIP1 for Proteasomal Degradation after UV Irradiation (cid:1) †
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紫外线照射可诱导p21 WAF 1/CIP 1蛋白通过泛素-蛋白酶体途径降解，但其生化机制尚不清楚。在这里，我们表明，丝氨酸-114磷酸化的p21蛋白的糖原合成酶激酶3（cid：1）（GSK-3（cid：1））是必需的，其降解响应于紫外线照射和GSK-3（cid：1）的激活是一个下游事件的ATR信号通路由UV触发。紫外线可使GSK-3（cid：1）活性短暂升高，这种升高可被咖啡因或ATR小干扰RNA阻断，表明GSK-3（cid：1）的ATR依赖性活化。位于推定的GSK-3（cid：1）靶序列内的ser-114在UV暴露时被GSK-3（cid：1）磷酸化。p21的非磷酸化的S114 A突变体被保护免受UV诱导的不稳定。p21蛋白的紫外线照射降解是独立的p53状态，并防止蛋白酶体抑制剂。与以前的报道相反，p21的蛋白酶体降解似乎是不依赖于泛素化的。这些数据显示GSK-3（cid：1）通过ATR信号传导途径被UV照射激活，并在ser-114处磷酸化p21，以使其被蛋白酶体降解。据我们所知，这是GSK-3（cid：1）作为UV诱导的ATR激活和p21降解之间缺失的环节的首次证明。
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 (cid:1) (GSK-3 (cid:1) ) is required for its degradation in response to UV irradiation and that GSK-3 (cid:1) activation is a downstream event in the ATR signaling pathway triggered by UV. UV transiently increased GSK-3 (cid:1) activity, and this increase could be blocked by caffeine or by ATR small interfering RNA, indicating ATR-dependent activation of GSK-3 (cid:1) . ser-114, located within the putative GSK-3 (cid:1) target sequence, was phosphorylated by GSK-3 (cid:1) 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 (cid:1) 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 (cid:1) as the missing link between UV-induced ATR activation and p21 degradation.