DeltaNp63诱导β-连环蛋白在细胞核内积聚并激活信号传导。

DeltaNp63 induces beta-catenin nuclear accumulation and signaling.

作者信息

Patturajan Meera, Nomoto Shuji, Sommer Matthias, Fomenkov Alexey, Hibi Kenji, Zangen Rachel, Poliak Nina, Califano Joseph, Trink Barry, Ratovitski Edward, Sidransky David

机构信息

Department of Otolaryngology-Head and Neck Surgery, John Hopkins School of Medicine, Baltimore, MD 21205, USA.

出版信息

Cancer Cell. 2002 May;1(4):369-79. doi: 10.1016/s1535-6108(02)00057-0.

DOI:10.1016/s1535-6108(02)00057-0

PMID:12086851

Abstract

The P53 homolog p63 encodes multiple proteins with transactivating, apoptosis-inducing, and oncogenic activities. We showed that p63 is amplified and that DeltaNp63 isotypes are overexpressed in squamous cell carcinoma (SCC) and enhance oncogenic growth in vitro and in vivo. Moreover, p53 associated with DeltaNp63alpha and mediated its degradation. Here, we report that DeltaNp63 associates with the B56alpha regulatory subunit of protein phosphatase 2A (PP2A) and glycogen synthase kinase 3beta (GSK3beta), leading to a dramatic inhibition of PP2A-mediated GSK3beta reactivation. The inhibitory effect of DeltaNp63 on GSK3beta mediates a decrease in phosphorylation levels of beta-catenin, which induces intranuclear accumulation of beta-catenin and activates beta-catenin-dependent transcription. Our results suggest that DeltaNp63 isotypes act as positive regulators of the beta-catenin signaling pathway, providing a basis for their oncogenic properties.

摘要

P53 同源物 p63 编码多种具有反式激活、诱导凋亡和致癌活性的蛋白质。我们发现 p63 在鳞状细胞癌（SCC）中发生扩增，且 ΔNp63 亚型过表达，并在体外和体内增强致癌生长。此外，p53 与 ΔNp63α 相关联并介导其降解。在此，我们报告 ΔNp63 与蛋白磷酸酶 2A（PP2A）的 B56α 调节亚基以及糖原合酶激酶 3β（GSK3β）相关联，导致 PP2A 介导的 GSK3β 再激活受到显著抑制。ΔNp63 对 GSK3β 的抑制作用介导了 β-连环蛋白磷酸化水平的降低，这诱导了 β-连环蛋白在细胞核内的积累并激活了 β-连环蛋白依赖性转录。我们的结果表明，ΔNp63 亚型作为 β-连环蛋白信号通路的正调控因子，为它们的致癌特性提供了基础。