Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
Hepatology. 2010 Nov;52(5):1808-18. doi: 10.1002/hep.23882.
Although the cytokine-inducible transcription factor signal transducer and activator of transcription 5 (STAT5) promotes proliferation of a wide range of cell types, there are cell-specific and context-specific cases in which loss of STAT5 results in enhanced cell proliferation. Here, we report that loss of STAT5 from mouse embryonic fibroblasts (MEFs) leads to enhanced proliferation, which was linked to reduced levels of the cell cycle inhibitors p15(INK4B) and p21(CIP1). We further demonstrate that growth hormone, through the transcription factor STAT5, enhances expression of the Cdkn2b (cyclin-dependent kinase inhibitor 2B) gene and that STAT5A binds to interferon-gamma-activated sequence sites within the promoter. We recently demonstrated that ablation of STAT5 from liver results in hepatocellular carcinoma upon CCl₄ treatment. We now establish that STAT5, like in MEFs, activates expression of the Cdkn2b gene in liver tissue. Loss of STAT5 led to diminished p15(INK4B) and increased hepatocyte proliferation.
This study for the first time demonstrates that cytokines, through STAT5, induce the expression of a key cell cycle inhibitor. These experiments therefore shed mechanistic light on the context-specific role of STAT5 as tumor suppressor.
尽管细胞因子诱导的转录因子信号转导子和转录激活子 5（STAT5）促进了广泛的细胞类型的增殖，但在细胞特异性和特定背景下，STAT5 的缺失会导致细胞增殖增强。在这里，我们报告说，从小鼠胚胎成纤维细胞（MEFs）中缺失 STAT5 会导致增殖增强，这与细胞周期抑制剂 p15（INK4B）和 p21（CIP1）水平降低有关。我们进一步证明，生长激素通过转录因子 STAT5 增强了 Cdkn2b（细胞周期蛋白依赖性激酶抑制剂 2B）基因的表达，并且 STAT5A 结合到启动子内干扰素-γ激活序列位点。我们最近证明，从肝脏中缺失 STAT5 会导致 CCl₄ 处理后的肝细胞癌。我们现在确定 STAT5 像在 MEFs 中一样，在肝组织中激活 Cdkn2b 基因的表达。STAT5 的缺失导致 p15（INK4B）减少和肝细胞增殖增加。
本研究首次证明细胞因子通过 STAT5 诱导关键细胞周期抑制剂的表达。因此，这些实验为 STAT5 作为肿瘤抑制因子的特定背景作用提供了机制上的解释。
