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

Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
Hepatology (Impact Factor: 11.06). 11/2010; 52(5):1808-18. DOI: 10.1002/hep.23882
Source: PubMed


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. 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.

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    • "Male and female wild-type C57BL/6 J mice and SHP-null mice were used in experiments. The study used null male mice for PDK4 (27,30), STAT5 (31), and SHP (16) (weight, 20–30 g; age, 12 weeks). Recombinant human GH (ProSpec, Rehovot, Israel) was administered intraperitoneally (i.p.) to fed mice at 2 μg/g body weight; metformin was given by oral gavage to fed mice at 200 mg/kg body weight. "
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    ABSTRACT: Growth hormone (GH) is a counter-regulatory hormone that plays an important role in preventing hypoglycemia during fasting. Because inhibition of the pyruvate dehydrogenase complex (PDC) by pyruvate dehydrogenase kinase 4 (PDK4) conserves substrates for gluconeogenesis, we tested whether GH increases PDK4 expression in liver by a signaling pathway sensitive to inhibition by metformin. The effects of GH and metformin were determined in the liver of wild-type, small heterodimer partner (SHP)-, PDK4-, and signal transducer and activator of transcription 5 (STAT5)-null mice. Administration of GH in vivo increased PDK4 expression via a pathway dependent on STAT5 phosphorylation. Metformin inhibited the induction of PDK4 expression by GH via a pathway dependent on AMP-activated protein kinase (AMPK) and SHP induction. The increase in PDK4 expression and PDC phosphorylation by GH was reduced in STAT5-null mice. Metformin decreased GH-mediated induction of PDK4 expression and metabolites in wild-type but not in SHP-null mice. In primary hepatocytes, dominant-negative mutant-AMPK and SHP knockdown prevented the inhibitory effect of metformin on GH-stimulated PDK4 expression. SHP directly inhibited STAT5 association on the PDK4 gene promoter. Metformin inhibits GH-induced PDK4 expression and metabolites via an AMPK-SHP-dependent pathway. The metformin-AMPK-SHP network may provide a novel therapeutic approach for the treatment of hepatic metabolic disorders induced by the GH-mediated pathway.
    Diabetes 06/2012; 61(10):2484-94. DOI:10.2337/db11-1665 · 8.10 Impact Factor
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    • "Furthermore, deletion of STAT5 in the liver promoted carbon tetrachloride-induced hepatic tumorigenesis in wild-type mice (Hosui et al., 2009) and induced spontaneous liver cancer development in liver-specific glucocorticoid receptor knockout mice (Mueller et al., 2011) or in GH transgenic mice (Friedbichler et al., 2012). The protective effect of STAT5 on hepatic carcinogenesis is likely mediated via the induction of a key cell cycle inhibitor–p15INK4B expression in hepatocytes (Yu et al., 2010) and protection against fatty liver disease and liver injury (Mueller et al., 2011; Friedbichler et al., 2012). "
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    ABSTRACT: Liver fibrosis, or cirrhosis, is a common end-stage condition of many chronic liver diseases after incomplete recovery from hepatocyte damage. During fibrosis progression, hepatocellular damage and inflammation trigger complex cellular events that result in collagen deposition and the disruption of the normal liver architecture. Hepatic stellate cell activation and transdifferentiation into myofibroblasts are key events in liver fibrogenesis. Research findings from cell culture and animal models have revealed that the Janus kinase-signal transducer and activator of transcription (Jak-STAT) signaling pathway, which can be activated by many cytokines, growth factors, and hormones, plays a critical role in hepatic fibrogenesis. This review summarizes the biological significance of diverse cytokines and their downstream signaling protein STATs in hepatic fibrogenesis.
    Frontiers in Physiology 04/2012; 3:69. DOI:10.3389/fphys.2012.00069 · 3.53 Impact Factor
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    • "Knockout studies in mice have indicated that p21 is required during stress hematopoiesis,119 and although p21 was also initially downregulated in STAT5 depleted LSK cells, this downmodulation was not maintained.88 On the other hand, in murine embryonic fibroblasts it has also been shown that STAT5 can negatively regulate cell cycle progression through activation of p21.120 Inhibition of JAK2/STAT5 signaling by the specific Jak2 inhibitor AZ960 stimulated cell cycling in CD34+/CD38− cells in conjunction with downregulation of p21.118 "
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    ABSTRACT: The level of transcription factor activity critically regulates cell fate decisions such as hematopoietic stem cell self-renewal and differentiation. The balance between hematopoietic stem cell self-renewal and differentiation needs to be tightly controlled, as a shift toward differentiation might exhaust the stem cell pool, while a shift toward self-renewal might mark the onset of leukemic transformation. A number of transcription factors have been proposed to be critically involved in governing stem cell fate and lineage commitment, such as Hox transcription factors, c-Myc, Notch1, β-catenin, C/ebpα, Pu.1 and STAT5. It is therefore no surprise that dysregulation of these transcription factors can also contribute to the development of leukemias. This review will discuss the role of STAT5 in both normal and leukemic hematopoietic stem cells as well as mechanisms by which STAT5 might contribute to the development of human leukemias.
    01/2012; 1(1):13-22. DOI:10.4161/jkst.19316
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