Wang Mingsheng, Liu Yiliang E, Goldberg Itzhak D, Shi Y Eric
Department of Radiation Oncology, Long Island Jewish Medical Center, The Long Island Campus for The Albert Einstein College of Medicine, New Hyde Park, NY 11040, USA.
J Biol Chem. 2003 Nov 21;278(47):47319-25. doi: 10.1074/jbc.M308131200. Epub 2003 Sep 15.
A mammary-derived growth inhibitor-related gene (MRG) was previously identified and characterized. MRG induces differentiation of mammary epithelial cells in vitro and its expression is associated with mammary differentiation. To further define the role of MRG on mammary gland differentiation, a MRG transgenic mice model under the control of mouse mammary tumor virus promoter was established and the effect of MRG on mammary gland differentiation was investigated at histological and molecular levels. Expression of endogenous mouse MRG gene was significantly increased from the non-differentiated gland of control virgin mice to the functionally differentiated gland of pregnant control mice. Whole mount analyses demonstrated that ductal development was not affected by MRG transgene expression. While there was no lobuloalveolar structure in control virgin mice, expression of MRG transgene in the mammary gland resulted in the development of lobuloalveolar-like structure, which mimics the gland from early pregnancy. Consistent with the morphological change, expression of MRG also increased milk protein beta-casein expression in the gland. To study the mechanism of MRG-induced mammary differentiation, we investigated the Stat5 activation in the glands from the transgenic mouse versus virgin control mouse. While activated Stat5 was expressed at the minimal level in the non-differentiated control virgin gland, a significant Stat5 phosphorylation was observed in the virgin transgenic gland. Our data indicate that MRG is a mediator of the differentiating effects of pregnancy on breast epithelium, and overexpression of MRG in young nulliparous mice can induce differentiation.
先前已鉴定并表征了一种乳腺衍生生长抑制因子相关基因（MRG）。MRG在体外可诱导乳腺上皮细胞分化，其表达与乳腺分化相关。为进一步明确MRG在乳腺分化中的作用，构建了在小鼠乳腺肿瘤病毒启动子控制下的MRG转基因小鼠模型，并从组织学和分子水平研究了MRG对乳腺分化的影响。从对照处女小鼠未分化的腺体到妊娠对照小鼠功能分化的腺体，内源性小鼠MRG基因的表达显著增加。整体装片分析表明，导管发育不受MRG转基因表达的影响。对照处女小鼠不存在小叶腺泡结构，而乳腺中MRG转基因的表达导致了类似小叶腺泡结构的发育，类似于妊娠早期的腺体。与形态学变化一致，MRG的表达也增加了腺体中乳蛋白β-酪蛋白的表达。为研究MRG诱导乳腺分化的机制，我们研究了转基因小鼠与处女对照小鼠腺体中Stat5的激活情况。在未分化的对照处女腺体中，活化的Stat5表达水平极低，而在处女转基因腺体中观察到显著的Stat5磷酸化。我们的数据表明，MRG是妊娠对乳腺上皮细胞分化作用的介导因子，在年轻未生育小鼠中过表达MRG可诱导分化。
