Bach1-mediated suppression of p53 is inhibited by p19ARF independently of MDM2
Bach1-mediated suppression of p53 is inhibited by p19ARF independently of MDM2
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DOI：
10.1111/j.1349-7006.2012.02244.x
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发表时间：
2012-05-01
期刊：
影响因子：
5.7
通讯作者：
Igarashi, Kazuhiko
中科院分区：
文献类型：
--
作者：
Nishizawa, Hironari;Ota, Kazushige;Igarashi, Kazuhiko
细胞衰老防止受损细胞的异常增殖。转录因子Bach 1与p53结合以抑制细胞衰老，但目前仍不清楚Bach 1 p53相互作用是如何调节的。我们发现Bach 1 p53相互作用被致癌Ras、博来霉素和过氧化氢抑制。Bach 1复合物的蛋白质组学分析揭示了其与p19 ARF的相互作用，p19 ARF是一种肿瘤抑制因子，当在细胞内过表达时，其竞争性抑制Bach 1 p53的相互作用。野生型小鼠胚胎成纤维细胞（MEFs）中MDM 2表达的减少并没有导致增殖减慢，这表明Bach 1在保持MEFs的增殖独立于MDM 2中发挥作用。与这种解释一致，当Bach 1和MDM 2都被废除时，MEFs中p21的表达被高度诱导。Bach 1蛋白水平在p53敲低时降低。这些结果表明，p53激活涉及其从Bach 1的解离，实现了部分通过竞争性结合p19 ARF Bach 1。p19 ARFBach 1相互作用构成了与p19 ARFMDM 2途径平行的p53调节途径。（Cancer Sci 2012; 103：897903）
Cellular senescence prevents the aberrant proliferation of damaged cells. The transcription factor Bach1 binds to p53 to repress cellular senescence, but it is still unclear how the Bach1p53 interaction is regulated. We found that the Bach1p53 interaction was inhibited by oncogenic Ras, bleomycin, and hydrogen peroxide. Proteomics analysis of Bach1 complex revealed its interaction with p19ARF, a tumor suppressor that competitively inhibited the Bach1p53 interaction when overexpressed within cells. Reduction of MDM2 expression in wild-type murine embryonic fibroblasts (MEFs) did not result in slower proliferation, showing that Bach1 plays a role in keeping the proliferation of MEFs independent of MDM2. Consistent with this interpretation, expression of p21 was highly induced in MEFs when both Bach1 and MDM2 were abrogated. The level of Bach1 protein was reduced on knockdown of p53. These results suggest that p53 activation involves its dissociation from Bach1, achieved in part by the competitive binding of p19ARF to Bach1. The p19ARFBach1 interaction constitutes a regulatory pathway of p53 in parallel with the p19ARFMDM2 pathway. (Cancer Sci 2012; 103: 897903)