SNF5, a core component of the SWI/SNF complex, is necessary for p53 expression and cell survival, in part through eIF4E.
SNF5, a core component of the SWI/SNF complex, is necessary for p53 expression and cell survival, in part through eIF4E.
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DOI：
10.1038/onc.2010.159
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发表时间：
2010-07-15
期刊：
影响因子：
8
通讯作者：
Chen, X.
中科院分区：
文献类型：
--
作者：
Xu, Y.;Yan, W.;Chen, X.
SNF 5是SWI/SNF染色质重塑复合物的核心组分，表达为两种亚型，SNF 5a和SNF 5 b。SNF 5是一种肿瘤抑制因子，因为SNF 5的突变导致肿瘤形成，并与p53缺陷协同增强癌症易感性。有趣的是，SNF 5的缺乏可能通过p53的异常激活抑制细胞存活和胚胎发育。为了进一步研究这一点，我们产生了SNF 5a、SNF 5 b或两者都可以被诱导敲低的细胞系。我们发现SNF 5敲除导致G1期细胞周期停滞，并且SNF 5a和SNF 5 b在功能上是冗余的。我们还表明，SNF 5敲低损害p21和MDM 2的p53依赖性转录。然而，与早期报道的在鼠细胞中通过SNF 5敲除激活p53相反，SNF 5敲除导致多种人细胞系中基础和应激诱导的p53表达降低，但不增加。此外，我们发现SNF 5敲低诱导AMPK活化并抑制eIF 4 E表达。最后，我们证明了SNF 5敲低通过eIF 4 E抑制p53翻译，并且在SNF 5敲低的细胞中替换eIF 4 E恢复p53表达和细胞存活。总之，我们的研究结果表明，p53通路的调节，并介导的活性，SNF 5在肿瘤抑制和促生存。
SNF5, a core component of the SWI/SNF chromatin remodeling complex, is expressed as two isoforms, SNF5a and SNF5b. SNF5 is a tumor suppressor as mutation of SNF5 leads to tumor formation and cooperates with p53 deficiency to enhance cancer susceptibility. Interestingly, lack of SNF5 inhibits cell survival and embryonic development potentially via abnormal activation of p53. To further examine this, we generated cell lines in that SNF5a, SNF5b, or both can be inducibly knocked down. We found that SNF5 knockdown leads to cell cycle arrest in G1, and SNF5a and SNF5b are functionally redundant. We also showed that SNF5 knockdown impairs p53-dependent transcription of p21 and MDM2. However, contrary to earlier reports that p53 is activated by SNF5 knockout in murine cells, SNF5 knockdown leads to decreased, but not increased, expression of both basal and stress-induced p53 in multiple human cell lines. In addition, we showed that SNF5 knockdown induces AMPK activation and inhibits eIF4E expression. Finally, we demonstrated that SNF5 knockdown inhibits p53 translation via eIF4E and replacement of eIF4E in SNF5-knockdown cells restores p53 expression and cell survival. Together, our results suggest that the p53 pathway is regulated by, and mediates the activity of, SNF5 in tumor suppression and pro-survival.
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DOI：
10.1073/pnas.250492697
发表时间：
2000-12-05
影响因子：
11.1
作者：
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通讯作者：
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影响因子：
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作者：
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