Wu Liqing, Zhu Hongyan, Nie Linghu, Maki Carl G
Department of Radiation and Cellular Oncology, The University of Chicago, 5841 S. Maryland Ave., MC1105, room G-06, Chicago, IL 60637, USA.
Oncogene. 2004 May 13;23(22):4032-6. doi: 10.1038/sj.onc.1207538.
The p53 family of proteins includes three members, p53, p63, and p73. The levels and stability of p53 are controlled in large part by MDM2, which can bind the p53 N-terminus and promote its degradation. Because the MDM2 gene is transcriptionally activated by p53, it forms part of an autoregulatory feedback loop that directly links the transcriptional activity of p53 with its degradation. In contrast, little is known about the mechanisms that control p63 or p73 stability. In the current study, p73 deletion or point mutants that lacked transactivation activity were stable compared to wild-type p73. A naturally occurring p73 variant (DeltaNp73) was also stable compared to wild-type p73. Finally, fusion of the VP16-transactivation domain to an inactive, stable p73 mutant restored transactivation function and rendered the mutant protein unstable. These results demonstrate that p73 transactivation activity is necessary for rapid p73 turnover, and suggest that one or more transcriptional targets of p73 may promote its degradation.
p53蛋白家族包括三个成员，即p53、p63和p73。p53的水平和稳定性在很大程度上受MDM2调控，MDM2可结合p53的N端并促进其降解。由于MDM2基因受p53转录激活，它构成了一个自调节反馈环的一部分，该反馈环直接将p53的转录活性与其降解联系起来。相比之下，关于调控p63或p73稳定性的机制知之甚少。在当前研究中，与野生型p73相比，缺乏反式激活活性的p73缺失或点突变体是稳定的。与野生型p73相比，一种天然存在的p73变体（DeltaNp73）也是稳定的。最后，将VP16反式激活结构域与无活性的稳定p73突变体融合可恢复反式激活功能，并使突变蛋白变得不稳定。这些结果表明，p73反式激活活性对于p73的快速周转是必需的，并提示p73的一个或多个转录靶点可能促进其降解。
