Sullivan Kelly D, Gallant-Behm Corrie L, Henry Ryan E, Fraikin Jean-Luc, Espinosa Joaquín M
Howard Hughes Medical Institute & Department of Molecular, Cellular and Developmental Biology, The University of Colorado at Boulder, Boulder, CO 80309-0347, USA.
Biochim Biophys Acta. 2012 Apr;1825(2):229-44. doi: 10.1016/j.bbcan.2012.01.004. Epub 2012 Feb 7.
The p53 tumor suppressor is embedded in a large gene network controlling diverse cellular and organismal phenotypes. Multiple signaling pathways converge onto p53 activation, mostly by relieving the inhibitory effects of its repressors, MDM2 and MDM4. In turn, signals originating from increased p53 activity diverge into distinct effector pathways to deliver a specific cellular response to the activating stimuli. Much attention has been devoted to dissecting how the various input pathways trigger p53 activation and how the activity of the p53 protein itself can be modulated by a plethora of co-factors and post-translational modifications. In this review we will focus instead on the multiple configurations of the effector pathways. We will discuss how p53-generated signals are transmitted, amplified, resisted and eventually integrated by downstream gene circuits operating at the transcriptional, post-transcriptional and post-translational levels. We will also discuss how context-dependent variations in these gene circuits define the cellular response to p53 activation and how they may impact the clinical efficacy of p53-based targeted therapies.
p53肿瘤抑制因子嵌入在一个控制多种细胞和机体表型的大型基因网络中。多条信号通路汇聚到p53的激活上，主要是通过解除其抑制因子MDM2和MDM4的抑制作用。反过来，源自p53活性增加的信号会分散到不同的效应器通路中，以对激活刺激产生特定的细胞反应。人们已经投入了大量精力来剖析各种输入通路如何触发p53激活，以及p53蛋白本身的活性如何被大量辅助因子和翻译后修饰所调节。在这篇综述中，我们将转而关注效应器通路的多种配置。我们将讨论p53产生的信号如何被转录、转录后和翻译后水平上运行的下游基因回路传递、放大、抵抗并最终整合。我们还将讨论这些基因回路中依赖于上下文的变化如何定义细胞对p53激活的反应，以及它们如何可能影响基于p53的靶向治疗的临床疗效。
