Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 985950 Nebraska Medical Center, Omaha, NE 68198-5950, USA.
Mol Cell Biol. 2010 Jun;30(12):2957-70. doi: 10.1128/MCB.00851-09. Epub 2010 Apr 12.
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.
信号转导子和转录激活子 5（Stat5）在乳腺上皮细胞的增殖、分泌分化和存活中发挥着关键作用。然而，关于促进这些生物学过程的 Stat5 靶基因的信息很少。我们在这里提供了实验证据，表明催乳素介导的 Stat5 磷酸化调节 Akt1 基因的转录激活。Stat5 以生长因子依赖性方式与 Akt1 基因座内的共有序列结合，从而从独特的启动子起始独特的 Akt1 mRNA 的转录，该启动子仅在乳腺中活跃。提高活性 Akt1 的水平可恢复 Jak2 缺陷型乳腺上皮细胞的 cyclin D1 表达和增殖，这表明 Akt1 作为 Jak/Stat 信号下游发挥作用。在转基因雌性动物中，配体诱导的 Stat5 表达在泌乳后 involution 开始时介导 Akt1 在乳腺上皮细胞中的持续上调。尽管诱导了促凋亡信号事件，但表达 Stat5 的乳腺表现出 involution 延迟。总的来说，本研究的结果阐明了活性 Stat5 介导逃避凋亡和生长信号自给自足的潜在机制。
