PIKE-A is required for prolactin-mediated STAT5a activation in mammary gland development
PIKE-A is required for prolactin-mediated STAT5a activation in mammary gland development
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DOI：
10.1038/emboj.2009.406
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发表时间：
2010-03-03
期刊：
影响因子：
11.4
通讯作者：
Ye, Keqiang
中科院分区：
文献类型：
--
作者：
Chan, Chi-Bun;Liu, Xia;Ye, Keqiang
PI3-激酶增强子A(Pike-A)在Akt信号通路的激活中起关键作用，在促进癌细胞存活方面具有重要作用。然而，人们对其生理功能知之甚少。在这里，我们证明了Pike-A直接与信号转导和转录激活因子5a(Stat5a)和催乳素(PRL)受体结合，后者是PRL诱导的Stat5a激活和随后的基因转录所必需的。去除HC11上皮细胞中的Pike-A可降低PRL诱导的STAT5激活和细胞周期蛋白D1的表达，从而严重损害体外培养的细胞增殖。为了确认Pike-A在体内PRL信号转导中的作用，我们建立了Pike基因敲除(Pike-/-)小鼠。Pike-/-小鼠表现出严重的哺乳缺陷，其特征是乳腺上皮细胞凋亡增加和增殖受阻。在分娩时，Pike-/-小鼠乳腺上皮细胞中STAT5的激活和细胞周期蛋白D1的表达显著减少。Pike-/-小鼠乳腺发育缺陷通过过表达乳腺特异的细胞周期蛋白D1基因得以挽救。这些数据为Pike-A在调节PRL功能中建立了一个关键功能。EMBO期刊(2010)29,956-968。DOI：10.1038/Intemj.2009.406；2010年1月14日在线发布
PI 3-kinase enhancer A (PIKE-A) is critical for the activation of Akt signalling, and has an essential function in promoting cancer cell survival. However, its physiological functions are poorly understood. Here, we show that PIKE-A directly associates with both signal transducer and activator of transcription 5a (STAT5a) and prolactin (PRL) receptor, which is essential for PRL-provoked STAT5a activation and the subsequent gene transcription. Depletion of PIKE-A in HC11 epithelial cells diminished PRL-induced STAT5 activation and cyclin D1 expression, resulting in profoundly impaired cell proliferation in vitro. To confirm the function of PIKE-A in PRL signalling in vivo, we generated PIKE knockout (PIKE-/-) mice. PIKE-/- mice displayed a severe lactation defect that was characterized by enhanced apoptosis and impaired proliferation of mammary epithelial cells. At parturition, STAT5 activation and cyclin D1 expression were substantially reduced in the mammary epithelium of PIKE-/- mice. The defective mammary gland development in PIKE-/- mice was rescued by overexpression of a mammary-specific cyclin D1 transgene. These data establish a critical function for PIKE-A in mediating PRL functions. The EMBO Journal (2010) 29, 956-968. doi: 10.1038/emboj.2009.406; Published online 14 January 2010