Stat5 Promotes Survival of Mammary Epithelial Cells through Transcriptional Activation of a Distinct Promoter in Akt1
Stat5 Promotes Survival of Mammary Epithelial Cells through Transcriptional Activation of a Distinct Promoter in Akt1
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DOI：
10.1128/mcb.00851-09
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发表时间：
2010-06-15
影响因子：
5.3
通讯作者：
Wagner, Kay-Uwe
中科院分区：
文献类型：
--
作者：
Creamer, Bradley A.;Sakamoto, Kazuhito;Wagner, Kay-Uwe
信号转导子和转录激活子5（Stat 5）在乳腺上皮细胞的增殖、分泌分化和存活中起关键作用。然而，关于促进这些生物学过程的Stat 5靶基因的信息很少。我们在这里提供的实验证据表明，催乳素介导的磷酸化Stat 5调节Akt 1基因的转录激活。Stat 5以生长因子依赖性方式与Akt 1基因座内的共有序列结合，以启动来自独特启动子的独特Akt 1 mRNA的转录，该启动子仅在乳腺中有活性。提高活性Akt 1的水平可以恢复细胞周期蛋白D1的表达和Jak 2缺陷型乳腺上皮细胞的增殖，这提供了Akt 1在Jak/Stat信号转导下游起作用的证据。在哺乳期后退化的发病过程中，Stat 5在转基因女性中的配体诱导表达介导了乳腺上皮细胞中Akt 1的持续上调。Stat 5表达乳腺表现出退化延迟，尽管诱导促凋亡信号传导事件。总的来说，本研究的结果阐明了一个潜在的机制，通过该机制，活性Stat 5介导逃避凋亡和自给自足的生长信号。
The signal transducer and activator of transcription 5 (Stat5) plays a pivotal role in the proliferation, secretory differentiation, and survival of mammary epithelial cells. However, there is little information about Stat5 target genes that facilitate these biological processes. We provide here experimental evidence that the prolactin-mediated phosphorylation of Stat5 regulates the transcriptional activation of the Akt1 gene. Stat5 binds to consensus sequences within the Akt1 locus in a growth factor-dependent manner to initiate transcription of a unique Akt1 mRNA from a distinct promoter, which is only active in the mammary gland. Elevating the levels of active Akt1 restores the expression of cyclin D1 and proliferation of Jak2-deficient mammary epithelial cells, which provides evidence that Akt1 acts downstream of Jak/Stat signaling. The ligand-inducible expression of Stat5 in transgenic females mediates a sustained upregulation of Akt1 in mammary epithelial cells during the onset of postlactational involution. Stat5-expressing mammary glands exhibit a delay in involution despite induction of proapoptotic signaling events. Collectively, the results of the present study elucidate an underlying mechanism by which active Stat5 mediates evasion from apoptosis and self-sufficiency in growth signals.