Insulin receptor substrate-1 expression is regulated by estrogen in the MCF-7 human breast cancer cell line
Insulin receptor substrate-1 expression is regulated by estrogen in the MCF-7 human breast cancer cell line
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DOI：
10.1074/jbc.275.17.12565
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发表时间：
2000-04-28
影响因子：
4.8
通讯作者：
Westley, BR
中科院分区：
文献类型：
--
作者：
Molloy, CA;May, FEB;Westley, BR
雌激素可以通过增加对胰岛素样生长因子的增殖反应来刺激雌激素反应性乳腺癌细胞的增殖。增加增殖的潜在机制可能涉及雌激素诱导胰岛素样生长因子信号转导途径的组分。在本研究中，我们检测了胰岛素受体底物-1的表达调节，胰岛素受体底物-1是I型胰岛素样生长因子受体酪氨酸激酶的主要细胞内底物，在与涉及雌激素受体的机制一致的浓度下，雌二醇增加胰岛素受体底物-1 mRNA和蛋白水平。胰岛素受体底物-1不被抗雌激素他莫昔芬和ICI 182，780显著诱导，但它们抑制雌二醇对胰岛素受体底物-1的诱导。酪氨酸磷酸化胰岛素受体底物-1的分析表明，最高水平被发现在细胞刺激的雌二醇和胰岛素样生长因子-I，而低水平被发现在没有雌二醇，无论是否存在I型胰岛素样生长因子配体。雌二醇对胰岛素受体底物-2、-3和-4无诱导作用。这些结果表明，雌激素和抗雌激素可能通过控制胰岛素受体底物-1的表达来调节细胞增殖，从而通过胰岛素样生长因子信号转导途径放大或减弱信号传导。
Estrogens can stimulate the proliferation of estrogen-responsive breast cancer cells by increasing their proliferative response to insulin-like growth factors. The mechanism underlying the increased proliferation could involve the induction of components of the insulin-like growth factor signal transduction pathway by estrogen, In this study we have examined the regulation of the expression of insulin receptor substrate-1, a major intracellular substrate of the type I insulin-like growth factor receptor tyrosine kinase, Estradiol increased insulin receptor substrate-1 mRNA and protein levels at concentrations consistent with a mechanism involving the estrogen receptor. Insulin receptor substrate-1 was not induced significantly by the antiestrogens tamoxifen and ICI 182,780, but they inhibited the induction of insulin receptor substrate-1 by estradiol. Analysis of tyrosine-phosphorylated insulin receptor substrate-1 showed that the highest levels were found in cells stimulated by estradiol and insulin-like growth factor-I, whereas low levels were found in the absence of estradiol irrespective of whether type I insulin-like growth factor ligands were present. Insulin receptor substrate-2, -3, and -4 were not induced by estradiol. These results suggest that estrogens and antiestrogens may regulate cell proliferation by controlling insulin receptor substrate-1 expression, thereby amplifying or attenuating signaling through the insulin-like growth factor signal transduction pathway.