p53 Isoforms: An Intracellular Microprocessor?
p53 Isoforms: An Intracellular Microprocessor?
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DOI：
10.1177/1947601911408893
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发表时间：
2011-04-01
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影响因子：
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通讯作者：
Bourdon, Jean-Christophe
中科院分区：
文献类型：
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作者：
Khoury, Marie P;Bourdon, Jean-Christophe
P53途径的正常功能在癌症中普遍丧失，要么是突变，要么是与病毒或细胞蛋白的相互作用失活。然而，在临床研究中，很难将P53突变状态与癌症治疗和临床结果联系起来，这表明人们对P53途径还没有完全了解。我们最近报道，由于选择性剪接、选择性启动翻译和选择性启动子的使用，人类p53基因不仅表达1种，而且表达12种不同的p53蛋白(亚型)。因此，P53异构体蛋白包含不同的蛋白结构域。它们在正常人体组织中表达，但在多种癌症类型中异常表达。我们最近报道了P53亚型的表达与乳腺癌的预后有关，提示它们在乳腺癌的发生中发挥了作用。事实上，细胞对损伤的反应可以通过只操纵P53亚型的表达而从细胞周期停滞切换到细胞凋亡。这可能为乳腺癌中p53突变、治疗反应和预后之间迄今不一致的关系提供了解释。然而，其分子机制仍不清楚。最近的报道表明，它涉及以P53依赖和非依赖的方式调节基因表达。在这篇综述中，我们总结了目前对P53亚型生物学活性的认识，并提出了一个分子机制来协调我们目前对P53的认识，并将P63和P73异构体整合到P53通路中。
Normal function of the p53 pathway is ubiquitously lost in cancers either through mutation or inactivating interaction with viral or cellular proteins. However, it is difficult in clinical studies to link p53 mutation status to cancer treatment and clinical outcome, suggesting that the p53 pathway is not fully understood. We have recently reported that the human p53 gene expresses not only 1 but 12 different p53 proteins (isoforms) due to alternative splicing, alternative initiation of translation, and alternative promoter usage. p53 isoform proteins thus contain distinct protein domains. They are expressed in normal human tissues but are abnormally expressed in a wide range of cancer types. We have recently reported that p53 isoform expression is associated with breast cancer prognosis, suggesting that they play a role in carcinogenesis. Indeed, the cellular response to damages can be switched from cell cycle arrest to apoptosis by only manipulating p53 isoform expression. This may provide an explanation to the hitherto inconsistent relationship between p53 mutation, treatment response, and outcome in breast cancer. However, the molecular mechanism is still unknown. Recent reports suggest that it involves modulation of gene expression in a p53-dependent and -independent manner. In this review, we summarize our current knowledge about the biological activities of p53 isoforms and propose a molecular mechanism conciliating our current knowledge on p53 and integrating p63 and p73 isoforms in the p53 pathway.