Liver degeneration and lymphoid deficiencies in mice lacking suppressor of cytokine signaling-1.

SOCS-1, a member of the suppressor of cytokine signaling (SOCS) family, was identified in a genetic screen for inhibitors of interleukin 6 signal transduction. SOCS-1 transcription is induced by cytokines, and the protein binds and inhibits Janus kinases and reduces cytokine-stimulated tyrosine phosphorylation of signal transducers and activators of transcription 3 and the gp130 component of the interleukin 6 receptor. Thus, SOCS-1 forms part of a feedback loop that modulates signal transduction from cytokine receptors. To examine the role of SOCS-1 in vivo, we have used gene targeting to generate mice lacking this protein. SOCS-1(-/-) mice exhibited stunted growth and died before weaning with fatty degeneration of the liver and monocytic infiltration of several organs. In addition, the thymus of SOCS-1(-/-) mice was reduced markedly in size, and there was a progressive loss of maturing B lymphocytes in the bone marrow, spleen, and peripheral blood. Thus, SOCS-1 is required for in vivo regulation of multiple cell types and is indispensable for normal postnatal growth and survival.

[1]  K Yuge,et al.  A Janus kinase inhibitor, JAB, is an interferon-gamma-inducible gene and confers resistance to interferons. , 1998, Blood.

[2]  C. Schindler.  STATs as activators of apoptosis. , 1998, Trends in cell biology.

[3]  W. Alexander,et al.  Twenty proteins containing a C-terminal SOCS box form five structural classes. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[4]  J. Darnell.  STATs and gene regulation. , 1997, Science.

[5]  I. Dusanter-Fourt,et al.  The structure, regulation and function of the Janus kinases (JAKs) and the signal transducers and activators of transcription (STATs). , 1997, European journal of biochemistry.

[6]  R. Flavell,et al.  Activation of the STAT signaling pathway can cause expression of caspase 1 and apoptosis , 1997, Molecular and cellular biology.

[7]  D. Greiner,et al.  Severe defects in immunity and hematopoiesis caused by SHP-1 protein-tyrosine-phosphatase deficiency. , 1997, Trends in biotechnology.

[8]  Warren S. Alexander,et al.  A family of cytokine-inducible inhibitors of signalling , 1997, Nature.

[9]  S. Akira,et al.  Structure and function of a new STAT-induced STAT inhibitor , 1997, Nature.

[10]  Takaho A. Endo,et al.  A new protein containing an SH2 domain that inhibits JAK kinases , 1997, Nature.

[11]  A. Yoshimura,et al.  CIS, a cytokine inducible SH2 protein, is a target of the JAK-STAT5 pathway and modulates STAT5 activation. , 1997, Blood.

[12]  H. Young,et al.  Bone marrow and thymus expression of interferon-gamma results in severe B-cell lineage reduction, T-cell lineage alterations, and hematopoietic progenitor deficiencies. , 1997, Blood.

[13]  W. Alexander,et al.  Point mutations within a dimer interface homology domain of c‐Mpl induce constitutive receptor activity and tumorigenicity. , 1995, The EMBO journal.

[14]  N. Copeland,et al.  A novel cytokine‐inducible gene CIS encodes an SH2‐containing protein that binds to tyrosine‐phosphorylated interleukin 3 and erythropoietin receptors. , 1995, The EMBO journal.

[15]  J. Mann,et al.  Expression and methylation of imprinted genes during in vitro differentiation of mouse parthenogenetic and androgenetic embryonic stem cell lines. , 1994, Development.

[16]  K. Yamamura,et al.  Chronic active hepatitis in transgenic mice expressing interferon-gamma in the liver. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[17]  Suzanne Cory,et al.  bcl-2 transgene inhibits T cell death and perturbs thymic self-censorship , 1991, Cell.

[18]  Nicos Nicola,et al.  Guidebook to cytokines and their receptors , 1994 .