一种缺失富含脯氨酸结构域的小鼠p53突变体可挽救Mdm4缺陷，并为Mdm2-Mdm4-p53调控网络提供了深入见解。

A mouse p53 mutant lacking the proline-rich domain rescues Mdm4 deficiency and provides insight into the Mdm2-Mdm4-p53 regulatory network.

作者信息

Toledo Franck, Krummel Kurt A, Lee Crystal J, Liu Chung-Wen, Rodewald Luo-Wei, Tang Mengjia, Wahl Geoffrey M

机构信息

The Salk Institute for Biological Studies, Gene Expression Laboratory, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.

出版信息

Cancer Cell. 2006 Apr;9(4):273-85. doi: 10.1016/j.ccr.2006.03.014.

DOI:10.1016/j.ccr.2006.03.014

Abstract

The mechanisms by which Mdm2 and Mdm4 (MdmX) regulate p53 remain controversial. We generated a mouse encoding p53 lacking the proline-rich domain (p53DeltaP). p53DeltaP exhibited increased sensitivity to Mdm2-dependent degradation and decreased transactivation capacity, correlating with deficient cell cycle arrest and reduced apoptotic responses. p53DeltaP induced lethality in Mdm2-/- embryos, but not in Mdm4-/- embryos. Mdm4 loss did not alter Mdm2 stability but significantly increased p53DeltaP transactivation to partially restore cycle control. In contrast, decreasing Mdm2 levels increased p53DeltaP levels without altering p53DeltaP transactivation. Thus, Mdm4 regulates p53 activity, while Mdm2 mainly controls p53 stability. Furthermore, Mdm4 loss dramatically improved p53DeltaP-mediated suppression of oncogene-induced tumors, emphasizing the importance of targeting Mdm4 in chemotherapies designed to activate p53.

摘要

Mdm2和Mdm4（MdmX）调节p53的机制仍存在争议。我们培育了一种编码缺乏富含脯氨酸结构域的p53（p53DeltaP）的小鼠。p53DeltaP对Mdm2依赖性降解的敏感性增加，反式激活能力降低，这与细胞周期停滞缺陷和凋亡反应减少相关。p53DeltaP在Mdm2基因敲除胚胎中诱导致死，但在Mdm4基因敲除胚胎中不诱导致死。Mdm4缺失不改变Mdm2稳定性，但显著增加p53DeltaP反式激活以部分恢复周期控制。相反，降低Mdm2水平增加p53DeltaP水平而不改变p53DeltaP反式激活。因此，Mdm4调节p53活性，而Mdm2主要控制p53稳定性。此外，Mdm4缺失显著改善p53DeltaP介导的癌基因诱导肿瘤的抑制，强调在旨在激活p53的化疗中靶向Mdm4的重要性。