PRAP1 is a novel executor of p53-dependent mechanisms in cell survival after DNA damage
PRAP1 is a novel executor of p53-dependent mechanisms in cell survival after DNA damage
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DOI：
10.1038/cddis.2012.180
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发表时间：
2012-12-01
影响因子：
9
通讯作者：
Hooi, S. C.
中科院分区：
文献类型：
--
作者：
Huang, B. H.;Zhuo, J. L.;Hooi, S. C.
p53在控制细胞机制以响应广泛的遗传毒性应激中具有关键作用。在DNA损伤期间，p53可以通过激活衰老或细胞周期停滞和DNA修复来促进细胞存活，以维持细胞存活的基因组完整性，或者指导细胞进行凋亡以消除广泛受损的细胞。p53执行这两种相反细胞命运的能力取决于p53下游不同的信号传导途径。在这项研究中，我们发现，在化疗药物，γ射线照射和过氧化氢诱导的DNA损伤条件下，p53上调一种新的蛋白质，富含脯氨酸的酸性蛋白1（PRAP 1）。我们鉴定了PRAP 1基因内含子1内的功能性p53反应元件，并使用ChIP检测表明这些区域与p53直接相互作用，表明PRAP 1是一种新的p53靶基因。p53诱导PRAP 1表达可能会促进癌细胞对5-FU等化疗药物的耐药性，因为PRAP 1的敲除会增加5-FU治疗后癌细胞的细胞凋亡。PRAP 1似乎通过诱导细胞周期停滞来保护细胞免于凋亡，这表明p53响应于DNA损伤剂诱导PRAP 1表达有助于癌细胞存活。我们的研究结果提供了一个更深入的了解机制的促生存作用的p53细胞毒性治疗。Cell Death and Disease（2012）3，e442; doi：10.1038/cddis.2012.180; 2012年12月13日在线发表
p53 has a crucial role in governing cellular mechanisms in response to a broad range of genotoxic stresses. During DNA damage, p53 can either promote cell survival by activating senescence or cell-cycle arrest and DNA repair to maintain genomic integrity for cell survival or direct cells to undergo apoptosis to eliminate extensively damaged cells. The ability of p53 to execute these two opposing cell fates depends on distinct signaling pathways downstream of p53. In this study, we showed that under DNA damage conditions induced by chemotherapeutic drugs, gamma irradiation and hydrogen peroxide, p53 upregulates a novel protein, proline-rich acidic protein 1 (PRAP1). We identified functional p53-response elements within intron 1 of PRAP1 gene and showed that these regions interact directly with p53 using ChIP assays, indicating that PRAP1 is a novel p53 target gene. The induction of PRAP1 expression by p53 may promote resistance of cancer cells to chemotherapeutic drugs such as 5-fluorouracil (5-FU), as knockdown of PRAP1 increases apoptosis in cancer cells after 5-FU treatment. PRAP1 appears to protect cells from apoptosis by inducing cell-cycle arrest, suggesting that the induction of PRAP1 expression by p53 in response to DNA-damaging agents contributes to cancer cell survival. Our findings provide a greater insight into the mechanisms underlying the pro-survival role of p53 in response to cytotoxic treatments. Cell Death and Disease (2012) 3, e442; doi:10.1038/cddis.2012.180; published online 13 December 2012