Activation of Stat5a and Stat5b by tyrosine phosphorylation is tightly linked to mammary gland differentiation.
Activation of Stat5a and Stat5b by tyrosine phosphorylation is tightly linked to mammary gland differentiation.
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DOI：
10.1210/mend.10.12.8961260
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发表时间：
1996-12
影响因子：
--
通讯作者：
Xiuwen Liu;G. Robinson;L. Hennighausen
中科院分区：
文献类型：
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作者：
Xiuwen Liu;G. Robinson;L. Hennighausen
信号转导子和转录激活子（Signal transducer and activator of transcription，Stat）5最初被鉴定为一种乳腺因子（mammary gland factor，MGF），可与乳蛋白基因的启动子序列结合并激活其转录。我们已经产生了针对Stat5a或Stat5b的同种型特异性抗体，并表明这两种同种型在处女，怀孕，哺乳和退化小鼠的乳腺组织中的蛋白质水平上以相似的量存在。相比之下，Stat5磷酸化在未成熟处女中非常低，在妊娠后期急剧上升，并在退化期间迅速下降。磷酸化后，Stat5a和Stat5b形成同源和异源二聚体。妊娠晚期Stat5磷酸化的诱导与乳蛋白基因的转录激活相关。利用电泳迁移率变动分析和超变动分析，我们证明了哺乳期检测到的DNA结合活性由Stat5a和Stat5b组成，而不是其他STAT。Stat5直接参与乳腺细胞分化的假设在发情周期和乳腺发育受损的转基因小鼠中进行了测试。雌性小鼠发情期乳腺腺泡细胞的瞬时分化和乳蛋白基因表达与Stat5的瞬时磷酸化相一致。在携带截短形式的细胞命运蛋白Int3的小鼠中，乳腺发育受损和乳蛋白基因表达水平极低与磷酸化和异源二聚体形成减少相关。
Signal transducer and activator of transcription (Stat)5 was originally identified as a mammary gland factor (MGF) that binds to promoter sequences of milk protein genes and activates their transcription. We have generated isoform-specific antibodies against Stat5a or Stat5b and show that both isoforms are present in similar amounts at the protein level in mammary tissues of virgin, pregnant, lactating, and involuting mice. In contrast, Stat5 phosphorylation is very low in immature virgins, rises sharply during late pregnancy, and declines rapidly during involution. Upon phosphorylation, Stat5a and Stat5b form homo- and heterodimers. The induction of Stat5 phosphorylation during late pregnancy correlates with the transcriptional activation of milk protein genes. Using electrophoretic mobility shift assay and supershift analysis, we demonstrated that the DNA-binding activity detected during lactation is composed of both Stat5a and Stat5b, but not of other STATs. The hypothesis that Stat5 is directly involved in mammary cell differentiation was tested in estrous cycle and in transgenic mice with impaired mammary development. Transient differentiation of mammary alveolar cells and milk protein gene expression during estrus in virgin female mice coincide with transient Stat5 phosphorylation. Impaired mammary development and very low levels of milk protein gene expression in mice carrying the truncated form of the cell fate protein Int3 correlated with reduced phosphorylation and heterodimer formation.