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Yu, Ji Hoon,Zhu, Bing‐,Mei,Wickre, Mark,Riedlinger, Gregory,Chen, Weiping,Hosui, Atsushi,Robinson, Gertraud W.,Hennighausen, Lothar Wiley Subscription Services, Inc., A Wiley Company 2010 Hepatology Vol.52 No.5
<P><B>Abstract</B></P><P>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<SUP>INK4B</SUP> and p21<SUP>CIP1</SUP>. We further demonstrate that growth hormone, through the transcription factor STAT5, enhances expression of the <I>Cdkn2b</I> (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<SUB>4</SUB> treatment. We now establish that STAT5, like in MEFs, activates expression of the <I>Cdkn2b</I> gene in liver tissue. Loss of STAT5 led to diminished p15<SUP>INK4B</SUP> and increased hepatocyte proliferation. <I>Conclusion:</I> 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)</P>
Kimura, Akiko,Martin, Cyril,Robinson, Gertraud W,Simone, James M,Chen, Weiping,Wickre, Mark C,O'Shea, John J,Hennighausen, Lothar American Society for Biochemistry and Molecular Bi 2010 The Journal of biological chemistry Vol.285 No.43
<P>Cytokines control the biology of hematopoietic stem cells (HSCs) and progenitor cells in part through the transcription factors STAT5A/B. To investigate the target genes of STAT5A/B activated by cytokines in HSCs and progenitors, we performed microarray analyses using Lineage(-) Sca-1(+) c-Kit(+) (KSL) cells in the presence and absence of STAT5A/B. Stimulation with a mixture containing IL-3, IL-6, stem cell factor, thrombopoietin, and Flt3 ligand induced Ccn3/Nov mRNA over 100-fold in WT (control) but not Stat5a/b-null KSL cells. CCN3/NOV is a positive regulator of human HSC self-renewal and development of committed blood cells. Without stimulation, the Ccn3/Nov signal level was low in control KSL cells similar to Stat5a/b-null KSL cells. To determine which cytokine activates the Ccn3/Nov gene, we analyzed Lineage(-) c-Kit(+) (KL) and 32D cells using quantitative PCR and ChIP assays. Although stimulation with a mixture lacking IL-3 prevented the induction of Ccn3/Nov in control KL cells, IL-3 alone could induce Ccn3/Nov mRNA in control KL and 32D cells. ChIP assays using 32D cells revealed IL-3-induced binding of STAT5A/B to a γ-interferon-activated sequences site in the Ccn3/Nov gene promoter. This is the first report that Ccn3/Nov is directly induced by cytokines through STAT5A/B.</P>
Stat5 is indispensable for the maintenance of <i>bcr/abl</i> -positive leukaemia
Hoelbl, Andrea,Schuster, Christian,Kovacic, Boris,Zhu, Bingmei,Wickre, Mark,Hoelzl, Maria A,Fajmann, Sabine,Grebien, Florian,Warsch, Wolfgang,Stengl, Gabriele,Hennighausen, Lothar,Poli, Valeria,Beug, WILEY-VCH Verlag 2010 EMBO molecular medicine Vol.2 No.3
<P>Tumourigenesis caused by the Bcr/Abl oncoprotein is a multi-step process proceeding from initial to tumour-maintaining events and finally results in a complex tumour-supporting network. A key to successful cancer therapy is the identification of critical functional nodes in an oncogenic network required for disease maintenance. So far, the transcription factors Stat3 and Stat5a/b have been implicated in <I>bcr/abl</I>-induced initial transformation. However, to qualify as a potential drug target, a signalling pathway must be required for the maintenance of the leukaemic state. Data on the roles of Stat3 or Stat5a/b in leukaemia maintenance are elusive. Here, we show that both, Stat3 and Stat5 are necessary for initial transformation. However, Stat5- but not Stat3-deletion induces G<SUB>0</SUB>/G<SUB>1</SUB> cell cycle arrest and apoptosis of imatinib-sensitive and imatinib-resistant stable leukaemic cells <I>in vitro</I>. Accordingly, Stat5-abrogation led to effective elimination of myeloid and lymphoid leukaemia maintenance <I>in vivo</I>. Hence, we identified Stat5 as a vulnerable point in the oncogenic network downstream of Bcr/Abl representing a case of non-oncogene addiction (NOA).</P>