Department of Pathology, University of Colorado Denver, Aurora, CO 80045, USA.
Mol Cell Endocrinol. 2010 May 5;319(1-2):129-42. doi: 10.1016/j.mce.2010.01.019. Epub 2010 Jan 18.
The observation that inherited mutations within BRCA1 result in breast and ovarian cancers suggests a functional relationship may exist between hormone signaling and BRCA1 function. We demonstrate that AKT activation promotes the expression of BRCA1 in response to estrogen and IGF-1 receptor signaling, and the rapid increase in BRCA1 protein levels appears to occur independently of new protein synthesis. Further, we identify a novel AKT phosphorylation site in BRCA1 at S694 which is responsive to activation of these signaling pathways. These data suggest AKT phosphorylation of BRCA1 increases total protein expression by preventing proteasomal degradation. AKT activation also appears to support nuclear localization of BRCA1, and co-expression of activated AKT with BRCA1 decreases radiation sensitivity, suggesting this interaction has functional consequences for BRCA1's role in DNA repair. Targets within this pathway could provide strategies for modulation of BRCA1 protein, which may prove therapeutically beneficial for breast and ovarian cancer treatment.
研究发现，BRCA1 中的遗传突变会导致乳腺癌和卵巢癌，这表明激素信号和 BRCA1 功能之间可能存在功能关系。我们证明 AKT 的激活促进了 BRCA1 在雌激素和 IGF-1 受体信号转导下的表达，BRCA1 蛋白水平的快速增加似乎独立于新的蛋白质合成。此外，我们在 BRCA1 的 S694 处鉴定出一个新的 AKT 磷酸化位点，该位点对这些信号通路的激活有反应。这些数据表明，AKT 通过防止蛋白酶体降解来磷酸化 BRCA1，从而增加总蛋白表达。AKT 的激活似乎也支持 BRCA1 的核定位，并且激活的 AKT 与 BRCA1 的共表达降低了辐射敏感性，这表明这种相互作用对 BRCA1 在 DNA 修复中的作用具有功能后果。该途径中的靶点可以为调节 BRCA1 蛋白提供策略，这可能对乳腺癌和卵巢癌的治疗具有治疗益处。
