Transcriptional repression by wild-type p53 utilizes histone deacetylases, mediated by interaction with mSin3a
Transcriptional repression by wild-type p53 utilizes histone deacetylases, mediated by interaction with mSin3a
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DOI：
10.1101/gad.13.19.2490
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发表时间：
1999-10-01
影响因子：
10.5
通讯作者：
George, DL
中科院分区：
文献类型：
--
作者：
Murphy, M;Ahn, J;George, DL
越来越多的证据表明，p53肿瘤抑制蛋白不仅可以激活基因转录，还可以抑制特定基因的表达。尽管最近的研究暗示了p53在细胞凋亡通路中的转录抑制功能，但这种活性的分子基础仍然知之甚少。这项研究为阐明这一机制迈出了第一步。我们报道了曲古抑素A (TSA)，一种组蛋白去乙酰化酶（hdac）抑制剂，可以消除p53抑制Map4和stathmin两种负调控基因转录的能力。与这一发现一致，我们报道p53在体内与hdac物理相关。这种相互作用不是直接的，而是由辅抑制因子mSin3a介导的。在体内，当Map4启动子优先与去乙酰化组蛋白结合时，可以发现野生型p53和mSin3a，而不是突变型p53，与Map4启动子结合。值得注意的是，用TSA抑制p53介导的转录抑制可显著抑制p53诱导的细胞凋亡。这些数据首次揭示了p53介导的转录抑制机制，并强调了p53蛋白诱导细胞凋亡的重要性。
There is growing evidence that the p53 tumor suppressor protein not only can function to activate gene transcription but also to repress the expression of specific genes. Although recent studies have implicated the transcriptional repression function of p53 in the pathway of apoptosis, the molecular basis of this activity remains poorly understood. This study takes a first step toward elucidating this mechanism. We report that trichostatin A (TSA), an inhibitor of histone deacetylases (HDACs), abrogates the ability of p53 to repress the transcription of two genes that it negatively regulates, Map4 and stathmin. Consistent with this finding, we report that p53 physically associates in vivo with HDACs. This interaction is not direct but, rather, is mediated by the corepressor mSin3a. Both wild-type p53 and mSin3a, but not mutant p53, can be found bound to the Map4 promoter at times when this promoter preferentially associates with deacetylated histones in vivo. Significantly, inhibition of p53-mediated transcriptional repression with TSA markedly inhibits apoptosis induction by p53. These data offer the first mechanistic insights for p53-mediated transcriptional repression and underscore the importance of this activity for apoptosis induction by this protein.