BRCA1-IRIS activates cyclin D1 expression in breast cancer cells by downregulating the JNK phosphatase DUSP3/VHR
BRCA1-IRIS activates cyclin D1 expression in breast cancer cells by downregulating the JNK phosphatase DUSP3/VHR
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DOI：
10.1002/ijc.22597
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发表时间：
2007-07-01
影响因子：
6.4
通讯作者：
ElShamy, Wael M.
中科院分区：
文献类型：
--
作者：
Hao, Lu;ElShamy, Wael M.
细胞周期蛋白D1在细胞周期进程中发挥重要作用。在乳腺癌中，Cyclin D1的表达通过几种机制失控。我们先前的研究表明，在乳腺癌细胞中，BRCA1-IRIS过表达会诱导Cyclin D1过表达，并促进细胞增殖。BRCA1-IRIS单独或与类固醇受体共激活剂联合作用于c-Jun/AP1预先结合的细胞周期蛋白D1启动子并激活其转录，可以解释BRCA1-IRIS和细胞周期蛋白D1在乳腺癌细胞中的高表达和细胞增殖的增强。我们在这里报道了BRCA1-IRIS激活Cyclin D1表达的另一种或一种互补途径。BRCA1-IRIS过表达降低了双特异性磷酸酶DUSP3/VHR的表达，DUSP3/VHR是包括c-jun氨基末端激酶在内的多种MAPK的内源性抑制物。虽然BRCA1-IRIS过表达的机制尚不清楚，但它足以在人乳腺上皮细胞模型中诱导Cyclin D1过表达。VHR共表达可阻断细胞周期蛋白D1的过度表达。此外，在两个同时高表达BRCA1-IRIS和Cyclin D1的乳腺癌细胞株(MCF-7和SKBR3)中，通过RNA干扰去除BRCA1-IRIS可通过提高VHR的表达水平来减弱Cyclin D1的表达。这些数据证明了BRCA1-IRIS在人类乳腺癌细胞周期控制中的关键作用，并表明BRCA1-IRIS的非调控表达可能减少对正常生理生长刺激的依赖，从而为肿瘤细胞提供生长优势和抵抗内分泌治疗的潜在机制。(C)2007年Wiley-Liss，Inc.
Cyclin D1 plays an important role in cell cycle progression. In breast cancer, Cyclin D1 expression is deregulated by several mechanisms. We previously showed that in breast cancer cells, overexpression of BRCA1-IRIS induces Cyclin D1 overexpression and increases cell proliferation. BRCA1-IRIS alone or in complex with steroid receptor co-activators was targeted to the cyclin D1 promoter pre-bound by the c-jun/AP1 and activated its transcription, which could explain the co-overexpression of BRCA1-IRIS and Cyclin D1 in breast cancer cells coupled with their increased proliferation. We report here an alternate or a complementary pathway by which BRCA1-IRIS activates Cyclin D1 expression. BRCA1-IRIS overexpression decreases the expression of the dual specificity phosphatase, DUSP3/VHR, an endogenous inhibitor of several MAPKs, including c-Jun N-terminal kinase. Although, the mechanism by which BRCA1-IRIS overexpression accomplishes that is not yet known, it is sufficient to induce Cyclin D1 overexpression in a human mammary epithelial cell model. Cyclin D1 overexpression could be blocked by co-overexpression of VHR in those cells. Furthermore, in 2 breast cancer cell lines that overexpress both BRCA1-IRIS and Cyclin D1 (MCF-7 and SKBR3) depletion of BRCA1-IRIS by RNA interference attenuated the expression of Cyclin D1 by elevating the expression level of VHR. These data demonstrate a critical role for BRCA1-IRIS in human breast cancer cell-cycle control and suggest that deregulated expression of BRCA1-IRIS is likely to reduce dependence on normal physiological growth stimuli, thereby providing a growth advantage to tumor cells and a potential mechanism of resistance to endocrine therapy. (C) 2007 Wiley-Liss, Inc.