Collaboration of signal transducer and activator of transcription 1 (STAT1) and BRCA1 in differential regulation of IFN-γ target genes
Collaboration of signal transducer and activator of transcription 1 (STAT1) and BRCA1 in differential regulation of IFN-γ target genes
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DOI：
10.1073/pnas.080469697
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发表时间：
2000-05-09
影响因子：
11.1
通讯作者：
Horvath, CM
中科院分区：
文献类型：
--
作者：
Ouchi, T;Lee, SW;Horvath, CM
ifn - γ的大部分活性是stat1介导的转录反应的结果。在这项研究中，我们发现BRCA1肿瘤抑制因子与STAT1协同作用，以差异激活ifn - γ靶基因子集的转录，并介导该细胞因子的生长抑制。经ifn - γ处理后，细胞周期蛋白依赖性激酶抑制剂p21WAF1的诱导被BRCA1协同激活。而IRF-1基因则不受影响。重要的是，突变BRCA1 5382C等位基因纯合的乳腺癌细胞中p21WAF1的差异诱导被破坏。生化分析表明，这种转录协同作用的机制涉及BRCA1 aa 502-802与STAT1的c端转录激活域之间的相互作用：包括Ser-727，其磷酸化对转录激活至关重要。值得注意的是，Ser-727突变的STAT1蛋白与BRCA1结合不良，这加强了Ser-727在STAT蛋白募集转录共激活因子中的重要性。这些发现揭示了BRCA1在ifn依赖性肿瘤监测系统中功能的新机制。
Most of the activities of IFN-gamma are the result of STAT1-mediated transcriptional responses. In this study, we show that the BRCA1 tumor suppressor acts in concert with STAT1 to differentially activate transcription of a subset of IFN-gamma target genes and mediates growth inhibition by this cytokine. After IFN-gamma treatment, induction of the cyclin-dependent kinase inhibitor, p21WAF1, was synergistically activated by BRCA1. whereas the IRF-1 gene was unaffected. Importantly, the differential induction of p21WAF1 was impaired in breast cancer cells homozygous for the mutant BRCA1 5382C allele. Biochemical analysis illustrated that the mechanism of this transcriptional synergy involves interaction between BRCA1 aa 502-802 and the C-terminal transcriptional activation domain of STAT1: including Ser-727 whose phosphorylation is crucial for transcriptional activation. Significantly, STAT1 proteins mutated at Ser-727 bind poorly to BRCA1, reinforcing the importance of Ser-727 in the recruitment of transcriptional coactivators by STAT proteins. These findings reveal a novel mechanism for BRCA1 function in the IFN-gamma-dependent tumor surveillance system.