Regulation of p53: intricate loops and delicate balances (Retracted Article)
Regulation of p53: intricate loops and delicate balances (Retracted Article)
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DOI：
10.1016/s0006-2952(02)01149-8
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发表时间：
2002-09-01
影响因子：
5.8
通讯作者：
Ben-Ze'ev, A
中科院分区：
文献类型：
--
作者：
Oren, M;Damalas, A;Ben-Ze'ev, A
P53肿瘤抑制蛋白提供了一种主要的抗癌防御机制，1)53基因是人类癌症中最常见的基因改变目标，这一事实凸显了这一点。最近的工作使人们认识到，p53位于一个非常复杂的信号通路网络的中心，该网络整合了各种细胞内和细胞外的输入。这个网络的一部分由一系列自动调节反馈环组成，其中P53与其他已知在决定细胞命运中发挥重要作用的蛋白质显示出非常复杂的相互作用。我们讨论了两个这样的环，一个涉及β连环蛋白，另一个以Akt/蛋白激酶B为中心。在这两种情况下，中心模块都是P53和小鼠双分钟2(MDM2)蛋白之间的相互作用，MDM2蛋白使P53失活，并将其作为快速蛋白质降解的靶点。去调控的β-连环蛋白可导致MDM2失活和P53积聚，而激活的P53可促进β-连环蛋白的降解和下调。同样，Akt可以通过增强MDM2来阻止P53的激活，而激活的P53可以通过几种不同的方式下调Akt。在每种情况下，循环的实际输出都是由其不同组件的相反效果之间的微妙平衡决定的。通常，这种平衡由同一小区内同时发生的其他信令过程决定。癌症特有的基因改变能够严重扭曲这一平衡，从而以促进肿瘤转化的方式压倒P53的肿瘤抑制作用。(C)2002 Elsevier Science Inc.保留所有权利。
The p53 tumor suppressor protein provides a major anti-cancer defense mechanism, as underscored by the fact that the 1)53 gene is the most frequent target for genetic alterations in human cancer. Recent work has led to the realization that p53 lies at the hub of a very complex network of signaling pathways, which integrate a variety of intracellular and extracellular inputs. Part of this network consists of an array of autoregulatory feedback loops, where p53 exhibits very intricate interactions with other proteins known to play important roles in the determination of cell fate. We discuss two such loops, one involving the beta catenin protein and the other centering on the Akt/protein kinase B. In both cases, the central module is the interplay between p53 and the murine double minute 2 (Mdm2) protein, which inactivates p53 and targets it for rapid proteolysis. Whereas deregulated beta catenin can lead to Mdm2 inactivation and p53 accumulation, active p53 can promote the degradation and downregulation of beta catenin. Similarly, Akt can block p53 activation by potentiating, Mdm2, whereas activated p53 can tune down Akt in several different ways. In each case, the actual output of the loop is determined by the delicate balance between the opposing effects of its different components. Often, this balance is dictated by additional signaling processes that occur simultaneously within the same cell. Genetic alterations characteristic of cancer are capable of severely distorting this balance, thereby overriding the tumor suppressor effects of p53 in a manner that facilitates neoplastic conversion. (C) 2002 Elsevier Science Inc. All rights reserved.