9021

SOCS3

ATOD4|CIS3|Cish3|SOCS-3|SSI-3|SSI3;suppressor of cytokine signaling 3;SOCS3;suppressor of cytokine signaling 3

STAT-induced STAT inhibitor 3|cytokine-inducible SH2 protein 3

17q25.3

protein-coding

suppressor of cytokine signaling 3 (SOCS3) down-regulates several signaling pathways in multiple cell types, and previous data suggest that SOCS3 may shut off cytokine activation at the early stages of liver regeneration (Campbell, J.S., L. Prichard, F. Schaper, J. Schmitz, A. Stephenson-Famy, M.E. Rosenfeld, G.M. Argast, P.C. Heinrich, and N. Fausto. 2001.J. Clin. Invest. 107:1285-1292). We developed Socs3 hepatocyte-specific knockout (Socs3 h-KO) mice to directly study the role of SOCS3 during liver regeneration after a two-thirds partial hepatectomy (PH). Socs3 h-KO mice demonstrate marked enhancement of DNA replication and liver weight restoration after PH in comparison with littermate controls. Without SOCS3, signal transducer and activator of transcription 3 (STAT3) phosphorylation is prolonged, and activation of the mitogenic extracellular signal-regulated kinase 1/2 (ERK1/2) is enhanced after PH. In vitro, we show that SOCS3 deficiency enhances hepatocyte proliferation in association with enhanced STAT3 and ERK activation after epidermal growth factor or interleukin 6 stimulation. Microarray analyses show that SOCS3 modulates a distinct set of genes, which fall into diverse physiological categories, after PH. Using a model of chemical-induced carcinogenesis, we found that Socs3 h-KO mice develop hepatocellular carcinoma at an accelerated rate. By acting on cytokines and multiple proliferative pathways, SOCS3 modulates both physiological and neoplastic proliferative processes in the liver and may act as a tumor suppressor.

suppressor of cytokine signaling 3 (SOCS3), as a key regulator of cytokine signaling, has the potential to modulate numerous cellular processes. Its involvement in inflammatory disease is well established, and there is increasing evidence for a role in breast cancer as a regulator of signal transducers and activators of transcription (STATs). Here we show that over-expression of SOCS3 markedly supresses STAT3 expression, and abrogates STAT5 phosphorylation, resulting in decreased cell proliferation in T47D breast cancer cells, and decreased proliferation and anchorage-independent growth in MCF7 cells. Using T47D cells, we elucidated the signaling pathways and transcription factors involved in SOCS3 expression in response to prolactin, a key mammotropic hormone. Quantitative real time PCR was used to examine SOCS3 mRNA expression, IP/WB was used to examine STAT phosphorylation, luciferase reporter assays, chromatin immunoprecipitation (ChIP) and gel shift assays allowed evaluation of cis-elements and trans-factors regulating SOCS3 expression. We demonstrate that prolactin-induced SOCS3 expression is STAT-dependant, predominantly involving STAT5, although STAT1 is also associated with the promoter. In addition, prolactin-induced SOCS3 promoter activation requires PKA-stimulated Sp1 binding to the GC-rich region of the promoter. Finally, we show that PRL-induced SOCS3 expression can be potentiated by co-treatment with PGE(2). This study demonstrates that SOCS3 acts as an anti-proliferative agent in breast cancer cells, and highlights the complexity of SOCS3 regulation and crosstalk.