Signal transducer and activator of transcription 3 activates CCAAT enhancer-binding protein δ gene transcription in G0 growth-arrested mouse mammary epithelial cells and in involuting mouse mammary gland
Signal transducer and activator of transcription 3 activates CCAAT enhancer-binding protein δ gene transcription in G0 growth-arrested mouse mammary epithelial cells and in involuting mouse mammary gland
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DOI：
10.1074/jbc.m004476200
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发表时间：
2000-09-15
影响因子：
4.8
通讯作者：
DeWille, J
中科院分区：
文献类型：
--
作者：
Hutt, JA;O'Rourke, JP;DeWille, J
CCAAT增强子结合蛋白(C/EBP)家族转录因子参与了多种组织中细胞增殖和分化的调节。C/EBP Delta参与调节小鼠乳腺上皮细胞G(0)生长停滞和凋亡。本研究表明，信号转导和转录激活因子3(STAT3)的激活，而不是STAT1或STAT5的激活，与HC11小鼠乳腺上皮细胞的G(0)生长停滞同时发生，但不发生在NIH3T3成纤维细胞中。启动子分析表明，在G(0)生长停滞过程中参与转录激活的C/EBP Delta启动子片段含有一个STAT3结合位点，该位点的突变消除了C/EBP Delta启动子对G(0)生长停滞的诱导能力。在HC11细胞G(0)生长停滞过程中，过表达STAT3可增加C/EBP Delta启动子活性，而在相同条件下，显性阴性的STAT3可降低C/EBP Delta启动子活性。无论是STAT3过表达还是显性负表达，都不影响生长中的HC11细胞和G(0)生长停滞的NIH3T3细胞中C/EBP Delta启动子的活性，表明这种作用是针对G(0)生长停滞的乳腺上皮细胞的。条带漂移分析和抗体干扰分析表明，STAT3在G(0)生长受阻的HC11细胞提取物和24小时消退的小鼠乳腺提取物中与C/EBP增量启动子中的急性时相反应元件特异结合。这些数据表明，STAT3在G(0)生长停滞的小鼠乳腺上皮细胞中激活C/EBP Delta转录，并在退化过程中与C/EBP Delta启动子结合，提出了STAT3激活的自分泌机制。
The CCAAT enhancer-binding protein (C/EBP) family of transcription factors is implicated in the regulation of cell proliferation and differentiation in a variety of tissues. C/EBP delta is involved in regulating G(0) growth arrest and apoptosis of mouse mammary epithelial cells. This study shows that activation of signal transducer and activator of transcription 3 (Stat3), but not activation of Stat1 or Stat5, occurs concurrently with G(0) growth arrest of HC11 mouse mammary epithelial cells, but not NIH 3T3 fibroblasts. Promoter analysis demonstrates that the C/EBP delta promoter fragment involved in transcriptional activation during G(0) growth arrest contains a Stat3 binding site and that mutation of this site eliminates the G(0) growth arrest inducibility of the C/EBP delta promoter. Overexpression of Stat3 increases C/EBP delta promoter activity during G(0) growth arrest of HC11 cells, whereas dominant negative Stat3 decreases C/EBP delta promoter activity under the same conditions. Neither Stat3 overexpression nor dominant negative Stat3 expression influences C/EBP delta promoter activity in growing HC11 cells or G(0) growth-arrested NIH3T3 cells, demonstrating that the effect is specific to G(0) growth arrest of mammary epithelial cells. Band shift assays and antibody interference assays demonstrate specific binding of Stat3 to the acute phase response element in the C/EBP delta promoter in G(0) growth-arrested HC11 cell extracts and 24 h involuting mouse mammary gland extracts. These data indicate that Stat3 activates C/EBP delta transcription in G(0) growth-arrested mouse mammary epithelial cells and binds to the C/EBP delta promoter during involution, An autocrine mechanism of Stat3 activation is proposed.