MDM2 and Fbw7 cooperate to induce p63 protein degradation following DNA damage and cell differentiation
MDM2 and Fbw7 cooperate to induce p63 protein degradation following DNA damage and cell differentiation
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DOI：
10.1242/jcs.061010
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发表时间：
2010-07-15
影响因子：
4
通讯作者：
Guerrini, Luisa
中科院分区：
文献类型：
--
作者：
Galli, Francesco;Rossi, Mariangela;Guerrini, Luisa
必须在分化或凋亡条件下实现对p63蛋白水平的严格控制。在这里，我们描述了一个新的调节途径的Delta Np 63 α蛋白。我们发现MDM 2在细胞核中结合Delta Np 63 α，促进其易位到细胞质。MDM 2核定位信号是Delta Np 63 α核输出和随后降解所需的，而MDM 2环指结构域是不稳定的。一旦通过MDM 2输出到细胞质，p63被Fbw 7 E3-泛素连接酶靶向降解。Fbw 7（也称为FBXW 7）对Delta Np 63 α的有效降解需要GSK 3激酶活性。通过缺失和点突变分析，我们已经确定了位于p63的α和β尾部的磷酸降解决定子，其是降解所需的。此外，我们表明，MDM 2或Fbw 7消耗抑制降解的内源性Δ Np 63 α暴露于紫外线照射，阿霉素和角质形成细胞分化的细胞。我们的研究结果表明，在DNA损伤和细胞分化后，MDM 2和Fbw 7可以合作调节促增殖Delta Np 63 α蛋白的水平。
Tight control of p63 protein levels must be achieved under differentiation or apoptotic conditions. Here, we describe a new regulatory pathway for the Delta Np63 alpha protein. We found that MDM2 binds Delta Np63 alpha in the nucleus promoting its translocation to the cytoplasm. The MDM2 nuclear localization signal is required for Delta Np63 alpha nuclear export and subsequent degradation, whereas the MDM2 ring-finger domain is dispensable. Once exported to the cytoplasm by MDM2, p63 is targeted for degradation by the Fbw7 E3-ubiquitin ligase. Efficient degradation of Delta Np63 alpha by Fbw7 (also known as FBXW7) requires GSK3 kinase activity. By deletion and point mutations analysis we have identified a phosphodegron located in the alpha and beta tail of p63 that is required for degradation. Furthermore, we show that MDM2 or Fbw7 depletion inhibits degradation of endogenous Delta Np63 alpha in cells exposed to UV irradiation, adriamycin and upon keratinocyte differentiation. Our findings suggest that following DNA damage and cellular differentiation MDM2 and Fbw7 can cooperate to regulate the levels of the pro-proliferative Delta Np63 alpha protein.