Laboratorio Nazionale CIB, AREA Science Park, Padriciano 99, Trieste, TS 34149, Italy.
Curr Pharm Des. 2011;17(6):578-90. doi: 10.2174/138161211795222667.
About half of all human tumors contain an inactivating mutation of p53, while in the remaining tumors, the p53 pathway is frequently abrogated by alterations of other components of its signaling pathway. In humans, the p53 tumor suppressor is part of a small gene family that includes two other members, p73 and p63, structurally and functionally related to p53. Accumulating evidences indicate that all p53-family proteins function as molecular hubs of a highly interconnected signaling network that coordinates cell proliferation, differentiation and death in response to physiological inputs and oncogenic stress. Therefore, not only the p53-pathway but the entire "p53-family pathway" is a primary target for cancer drug development. In particular, the p53-related protein p73 has a crucial role in determining cellular responses to chemotherapy, and can vicariate p53 functions in triggering cell death after DNA damage in multiple experimental models. The biology and regulation of p73 is complex, since the TP73 gene incorporates both tumor-suppressive and proto-oncogenic functions. However, the p73 gene is rarely mutated in tumors, so appropriate pharmacological manipulation of the p73 pathway is a very promising approach for cancer therapy. Here we provide an overview of the principal mechanism of p73 regulation, and describe several examples of pharmacological tools that can induce p73 accumulation and function by acting on upstream p73 modulators or displacing inhibitory p73 interactors. A better understanding of how the p73 pathway works is mandatory to discover additional players intervening in this pathway and has important implications for the improvement of cancer treatment with the development of new molecules or with the reposition of currently available drugs.
大约一半的人类肿瘤包含 p53 的失活突变，而在其余肿瘤中，p53 通路经常被其信号通路的其他成分的改变所破坏。在人类中，p53 肿瘤抑制因子是一个小基因家族的一部分，该家族包括另外两个成员，p73 和 p63，它们在结构和功能上与 p53 相关。越来越多的证据表明，所有 p53 家族蛋白都作为一个高度相互关联的信号网络的分子枢纽发挥作用，该网络协调细胞增殖、分化和死亡，以响应生理输入和致癌应激。因此，不仅是 p53 通路，而且整个“p53 家族通路”都是癌症药物开发的主要靶点。特别是，与 p53 相关的蛋白 p73 在决定细胞对化疗的反应中起着至关重要的作用，并且可以在多个实验模型中在 DNA 损伤后触发细胞死亡时替代 p53 功能。p73 的生物学和调节非常复杂，因为 TP73 基因包含肿瘤抑制和原癌基因功能。然而，p73 基因在肿瘤中很少发生突变，因此适当的药理学操纵 p73 通路是癌症治疗的一种很有前途的方法。本文提供了 p73 调节的主要机制概述，并描述了几种药理学工具的例子，这些工具可以通过作用于上游 p73 调节剂或置换抑制性 p73 相互作用物来诱导 p73 积累和功能。更好地了解 p73 通路的工作机制对于发现干预该通路的其他参与者至关重要，并且对于通过开发新分子或重新定位现有药物来改善癌症治疗具有重要意义。
