p53 oligomerization status modulates cell fate decisions between growth, arrest and apoptosis
p53 oligomerization status modulates cell fate decisions between growth, arrest and apoptosis
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DOI：
10.1080/15384101.2016.1241917
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发表时间：
2016-01-01
期刊：
影响因子：
4.3
通讯作者：
Gariepy, Jean
中科院分区：
文献类型：
--
作者：
Fischer, Nicholas W.;Prodeus, Aaron;Gariepy, Jean
p53寡聚化结构域的突变与Li-Fraumeni综合征的癌症易感性有遗传联系这些突变通常改变p53的寡聚状态并损害其转录活性。通过四聚化激活p53是其肿瘤抑制功能所必需的，其通过诱导转录程序导致细胞命运决定，例如细胞周期停滞或细胞凋亡。p53如何在这些细胞命运结果之间做出选择仍不清楚。在这里，我们使用5个寡聚体的p53，包括2个新的p53结构，产生单体，二聚体或四聚体形式的p53，并证明他们诱导不同的细胞活性和基因表达谱，导致不同的细胞命运的结果。我们报告说，二聚体p53的变体是细胞生长抑制，可以逮捕细胞生长，但缺乏能力，触发p53无效细胞凋亡。相比之下，p53四聚体诱导快速凋亡和细胞生长停滞，而单体变体在功能上是无活性的，支持细胞生长。特别地，促停滞CDKN 1A和促凋亡P53 AIP 1基因的表达是重要的细胞命运决定因素，其由p53的寡聚状态差异调节。这项研究表明，最丰富的寡聚物种的p53存在于静息细胞，即p53二聚体，既不促进细胞生长或细胞死亡，并转移的寡聚状态平衡的p53在细胞中的单体或四聚体是一个关键参数，在p53为基础的细胞命运的决定。
Mutations in the oligomerization domain of p53 are genetically linked to cancer susceptibility in Li-Fraumeni Syndrome. These mutations typically alter the oligomeric state of p53 and impair its transcriptional activity. Activation of p53 through tetramerization is required for its tumor suppressive function by inducing transcriptional programs that lead to cell fate decisions such as cell cycle arrest or apoptosis. How p53 chooses between these cell fate outcomes remains unclear. Here, we use 5 oligomeric variants of p53, including 2 novel p53 constructs, that yield either monomeric, dimeric or tetrameric forms of p53 and demonstrate that they induce distinct cellular activities and gene expression profiles that lead to different cell fate outcomes. We report that dimeric p53 variants are cytostatic and can arrest cell growth, but lack the ability to trigger apoptosis in p53-null cells. In contrast, p53 tetramers induce rapid apoptosis and cell growth arrest, while a monomeric variant is functionally inactive, supporting cell growth. In particular, the expression of pro-arrest CDKN1A and pro-apoptotic P53AIP1 genes are important cell fate determinants that are differentially regulated by the oligomeric state of p53. This study suggests that the most abundant oligomeric species of p53 present in resting cells, namely p53 dimers, neither promote cell growth or cell death and that shifting the oligomeric state equilibrium of p53 in cells toward monomers or tetramers is a key parameter in p53-based cell fate decisions.