Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan.
Cancer Sci. 2012 May;103(5):897-903. doi: 10.1111/j.1349-7006.2012.02244.x. Epub 2012 Apr 11.
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 Bach1-p53 interaction is regulated. We found that the Bach1-p53 interaction was inhibited by oncogenic Ras, bleomycin, and hydrogen peroxide. Proteomics analysis of Bach1 complex revealed its interaction with p19(ARF), a tumor suppressor that competitively inhibited the Bach1-p53 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 p19(ARF) to Bach1. The p19(ARF)-Bach1 interaction constitutes a regulatory pathway of p53 in parallel with the p19(ARF)-MDM2 pathway.
细胞衰老可防止受损细胞的异常增殖。转录因子 Bach1 与 p53 结合以抑制细胞衰老，但 Bach1-p53 相互作用如何受到调节仍不清楚。我们发现 Bach1-p53 相互作用受到致癌性 Ras、博来霉素和过氧化氢的抑制。Bach1 复合物的蛋白质组学分析显示其与 p19(ARF)相互作用，p19(ARF)是一种肿瘤抑制因子，当在细胞内过表达时，会竞争性抑制 Bach1-p53 相互作用。在野生型小鼠胚胎成纤维细胞 (MEF) 中降低 MDM2 的表达不会导致增殖减慢，表明 Bach1 在保持 MEF 的增殖方面发挥作用，而与 MDM2 无关。与这一解释一致的是，当 Bach1 和 MDM2 都被废除时，p21 在 MEF 中的表达被高度诱导。p53 的敲低降低了 Bach1 蛋白的水平。这些结果表明，p53 的激活涉及到它与 Bach1 的解离，部分通过 p19(ARF)与 Bach1 的竞争性结合来实现。p19(ARF)-Bach1 相互作用构成了 p53 的调控途径，与 p19(ARF)-MDM2 途径平行。
