Restoring p53 Function in Human Melanoma Cells by Inhibiting MDM2 and Cyclin B1/CDK1-Phosphorylated Nuclear iASPP
Restoring p53 Function in Human Melanoma Cells by Inhibiting MDM2 and Cyclin B1/CDK1-Phosphorylated Nuclear iASPP
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DOI：
10.1016/j.ccr.2013.03.013
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发表时间：
2013-05-13
期刊：
影响因子：
50.3
通讯作者：
Lu, Xin
中科院分区：
文献类型：
--
作者：
Lu, Min;Breyssens, Hilde;Lu, Xin
近90%的人类黑色素瘤含有失活的野生型p53，其潜在机制尚未完全了解。在这里，我们确定细胞周期蛋白B1/CDK 1磷酸化iASPP，这导致抑制iASPP二聚化，促进iASPP单体核进入，并暴露其p53结合位点，导致p53抑制增加。核iASPP在黑色素瘤转移中富集，并与患者生存率低相关。大多数表达野生型p53的黑色素瘤细胞系共表达高水平的磷酸化核iASPP、MDM 2和细胞周期蛋白B1。用小分子抑制MDM 2和iASPP磷酸化诱导p53依赖性凋亡和生长抑制。同时p53再激活和BRAFV 600 E抑制在体内实现了叠加抑制，为黑色素瘤治疗提供了一种替代方案。
Nearly 90% of human melanomas contain inactivated wild-type p53, the underlying mechanisms for which are not fully understood. Here, we identify that cyclin B1/CDK1-phosphorylates iASPP, which leads to the inhibition of iASPP dimerization, promotion of iASPP monomer nuclear entry, and exposure of its p53 binding sites, leading to increased p53 inhibition. Nuclear iASPP is enriched in melanoma metastasis and associates with poor patient survival. Most wild-type p53-expressing melanoma cell lines coexpress high levels of phosphorylated nuclear iASPP, MDM2, and cyclin B1. Inhibition of MDM2 and iASPP phosphorylation with small molecules induced p53-dependent apoptosis and growth suppression. Concurrent p53 reactivation and BRAFV600E inhibition achieved additive suppression in vivo, presenting an alternative for melanoma therapy.