BRCA1 and c-Myc associate to transcriptionally repress psoriasin, a DNA damage-inducible gene
BRCA1 and c-Myc associate to transcriptionally repress psoriasin, a DNA damage-inducible gene
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DOI：
10.1158/0008-5472.can-05-1841
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发表时间：
2005-11-15
期刊：
影响因子：
11.2
通讯作者：
Harkin, DP
中科院分区：
文献类型：
--
作者：
Kennedy, RD;Gorski, JJ;Harkin, DP
越来越多的证据表明，与BRCA1相关的一些不同功能可能与其转录调节关键下游靶基因的能力有关。在这里，我们确定了S100A钙结合蛋白家族成员S100A7（牛皮癣蛋白）、S100A8和S100A9作为新的brca1抑制靶点。我们发现功能性BRCA1是抑制这些家族成员的必要条件，并且BRCA1疾病相关突变可消除BRCA1介导的银屑病抑制。此外，我们发现BRCA1和c-Myc在银屑病蛋白启动子上形成复合物，BRCA1介导的银屑病蛋白抑制依赖于功能性的c-Myc。最后，我们发现在缺乏功能性BRCA1的情况下，拓扑异构酶II α毒素依托泊苷可诱导银屑病蛋白的表达，银屑病蛋白表达的增加可增强细胞对该化疗药物的敏感性。因此，我们确定了一种新的转录机制，可能有助于brca1介导的对依托泊苷的抗性。
Evidence is accumulating to suggest that some of the diverse functions associated with BRCA1 may relate to its ability to transcriptionally regulate key downstream target genes. Here, we identify, S100A7 (psoriasin), S100A8, and S100A9, members of the S100A family of calcium-binding proteins, as novel BRCA1-repressed targets. We show that functional BRCA1 is required for repression of these family members and that a BRCA1 disease-associated mutation abrogates BRCA1-mediated repression of psoriasin. Furthermore, we show that BRCA1 and c-Myc form a complex on the psoriasin promoter and that BRCA1-mediated repression of psoriasin is dependent on functional c-Myc. Finally, we show that psoriasin expression is induced by the topoisomerase II alpha poison, etoposide, in the absence of functional BRCA1 and increased psoriasin expression enhances cellular sensitivity to this chemotherapeutic agent. Therefore, we identified a novel transcriptional mechanism that is likely to contribute to BRCA1-mediated resistance to etoposide.