肌醇多聚磷酸激酶是 p53 介导的转录和细胞死亡的共激活因子。
Inositol polyphosphate multikinase is a coactivator of p53-mediated transcription and cell death.
机构信息
Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
出版信息
Sci Signal. 2013 Apr 2;6(269):ra22. doi: 10.1126/scisignal.2003405.
Abstract
The tumor suppressor protein p53 is a critical stress response transcription factor that induces the expression of genes leading to cell cycle arrest, apoptosis, and tumor suppression. We found that mammalian inositol polyphosphate multikinase (IPMK) stimulated p53-mediated transcription by binding to p53 and enhancing its acetylation by the acetyltransferase p300 independently of its inositol phosphate and lipid kinase activities. Genetic or RNA interference (RNAi)-mediated knockdown of IPMK resulted in decreased activation of p53, decreased recruitment of p53 and p300 to target gene promoters, abrogated transcription of p53 target genes, and enhanced cell viability. Additionally, blocking the IPMK-p53 interaction decreased the extent of p53-mediated transcription. These results suggest that IPMK acts as a transcriptional coactivator for p53 and that it is an integral part of the p53 transcriptional complex facilitating cell death.
摘要
肿瘤抑制蛋白 p53 是一种关键的应激反应转录因子，它诱导导致细胞周期停滞、细胞凋亡和肿瘤抑制的基因表达。我们发现，哺乳动物肌醇多磷酸激酶（IPMK）通过与 p53 结合并增强乙酰转移酶 p300 的乙酰化作用来刺激 p53 介导的转录，而不依赖于其肌醇磷酸盐和脂质激酶活性。IPMK 的遗传或 RNA 干扰（RNAi）介导的敲低导致 p53 的激活减少，p53 和 p300 向靶基因启动子的募集减少，p53 靶基因的转录被阻断，细胞活力增强。此外，阻断 IPMK-p53 相互作用会降低 p53 介导的转录程度。这些结果表明，IPMK 作为 p53 的转录共激活因子发挥作用，是促进细胞死亡的 p53 转录复合物的一个组成部分。
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1
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Nat Rev Cancer. 2013 Feb;13(2):83-96. doi: 10.1038/nrc3430. Epub 2013 Jan 10.
2
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J Biol Chem. 2012 Nov 2;287(45):38347-55. doi: 10.1074/jbc.M112.384255. Epub 2012 Sep 19.
3
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J Biol Chem. 2012 Oct 12;287(42):35360-35369. doi: 10.1074/jbc.M112.365031. Epub 2012 Aug 15.
4
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5
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6
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7
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8
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9
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10
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