Developmental and hormonal signals dramatically alter the localization and abundance of insulin receptor substrate proteins in the mammary gland
Developmental and hormonal signals dramatically alter the localization and abundance of insulin receptor substrate proteins in the mammary gland
复制标题
DOI：
10.1210/en.2002-221103
复制
发表时间：
2003-06-01
期刊：
影响因子：
4.8
通讯作者：
Hadsell, DL
中科院分区：
文献类型：
--
作者：
Lee, AV;Zhang, P;Hadsell, DL
胰岛素受体底物（IRS）是激素、细胞因子和生长因子信号传导的中心整合剂。IRS蛋白可以通过许多对正常乳腺发育至关重要的信号通路磷酸化。在乳腺中过表达IGF-I的转基因小鼠中的研究表明，IRS表达在正常哺乳后乳腺退化的调节中是重要的。这些研究的目的是检查IRS在小鼠乳腺中的表达，并确定IRS-1对未交配小鼠乳腺发育的重要性。IRS-1和IRS-2在处女小鼠乳腺中显示出不同的蛋白表达模式，并且蛋白丰度在妊娠和哺乳期间显著增加，但在退化期间迅速丢失。与激素调节一致，IRS-1蛋白水平通过卵巢切除术降低，通过雌激素和孕酮的联合治疗诱导，并且在整个发情周期中变化很大。这些变化发生在mRNA水平没有类似的变化，这表明转录后控制。IRS-1缺失小鼠的乳腺具有比野生型对照更小的脂肪垫，但这种减少与身体大小的总体减少成比例。IRS-1的缺失不会改变乳腺导管（末端芽和分支点）的发育，妊娠诱导的增殖也不会改变。这些数据表明，IRS在乳腺中经历复杂的发育和激素调节，IRS-1更可能调节哺乳期小鼠的乳腺功能，而不是处女或妊娠小鼠。
Insulin receptor substrates (IRS) are central integrators of hormone, cytokine, and growth factor signaling. IRS proteins can be phosphorylated by a number of signaling pathways critical to normal mammary gland development. Studies in transgenic mice that overexpress IGF-I in the mammary gland suggested that IRS expression is important in the regulation of normal postlactational mammary involution. The goal of these studies was to examine IRS expression in the mouse mammary gland and determine the importance of IRS-1 to mammary development in the virgin mouse. IRS-1 and -2 show distinct patterns of protein expression in the virgin mouse mammary gland, and protein abundance is dramatically increased during pregnancy and lactation, but rapidly lost during involution. Consistent with hormone regulation, IRS-1 protein levels are reduced by ovariectomy, induced by combined treatment with estrogen and progesterone, and vary considerably throughout the estrous cycle. These changes occur without similar changes in mRNA levels, suggesting post-transcriptional control. Mammary glands from IRS-1 null mice have smaller fat pads than wild-type controls, but this reduction is proportional to the overall reduction in body size. Development of the mammary duct (terminal endbuds and branch points) is not altered by the loss of IRS-1, and pregnancy-induced proliferation is not changed. These data indicate that IRS undergo complex developmental and hormonal regulation in the mammary gland, and that IRS-1 is more likely to regulate mammary function in lactating mice than in virgin or pregnant mice.