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The transcription factors signal transducer and activator of transcription 5A (STAT5A) and STAT5B negatively regulate cell proliferation through the activation of cyclin‐dependent kinase inhibitor 2b ( Cdkn2b ) and Cdkn1a expression
Author(s) -
Yu Ji Hoon,
Zhu BingMei,
Wickre Mark,
Riedlinger Gregory,
Chen Weiping,
Hosui Atsushi,
Robinson Gertraud W.,
Hennighausen Lothar
Publication year - 2010
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.23882
Subject(s) - stat5 , cell growth , cancer research , stat protein , biology , cyclin d , microbiology and biotechnology , transcription factor , stat3 , cell cycle , cyclin dependent kinase , signal transduction , cell , gene , genetics , biochemistry
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 CCl 4 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. Conclusion: 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. (HEPATOLOGY 2010;52:1808‐1818)