Physiological significance of STAT proteins: investigations through gene disruption in vivo.

Signal transducers and activators of transcription (STATs) were discovered as mediators of type I interferon-induced gene expression. This family of transcription factors has been found in widespread signaling pathways, especially those involving cytokines regulating the immune response. Because a plethora and often confusing set of activators for STAT proteins was observed in cell culture models, it became important to define the physiologically relevant actions of these molecules. One approach to this question has been through the targeted disruption of STAT genes in transgenic mice. Now that all seven STAT genes have been disrupted, both the high degree of STAT selectivity as well as many surprising and unexpected complexities are beginning to be characterized.

[1]  K. Shiota,et al.  Targeted disruption of gp130, a common signal transducer for the interleukin 6 family of cytokines, leads to myocardial and hematological disorders. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[2]  Allard Kaptein,et al.  Dominant Negative Stat3 Mutant Inhibits Interleukin-6-induced Jak-STAT Signal Transduction (*) , 1996, The Journal of Biological Chemistry.

[3]  R. Zinkernagel,et al.  Immune response in mice that lack the interferon-gamma receptor. , 1993, Science.

[4]  D. Levy,et al.  Targeted Disruption of the Mouse Stat1 Gene Results in Compromised Innate Immunity to Viral Disease , 1996, Cell.

[5]  R. Schreiber,et al.  Disruption of the Jak1 Gene Demonstrates Obligatory and Nonredundant Roles of the Jaks in Cytokine-Induced Biologic Responses , 1998, Cell.

[6]  M. Kaplan,et al.  Impaired IL-12 responses and enhanced development of Th2 cells in Stat4-deficient mice , 1996, Nature.

[7]  R. Snell,et al.  Requirement of STAT5b for sexual dimorphism of body growth rates and liver gene expression. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[8]  J. Darnell,et al.  Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. , 1994, Science.

[9]  A. Satoskar,et al.  Mice with STAT6-targeted gene disruption develop a Th1 response and control cutaneous leishmaniasis. , 1998, Journal of immunology.

[10]  Kenneth M. Murphy,et al.  Functional diversity of helper T lymphocytes , 1996, Nature.

[11]  J. Ihle,et al.  Stat5 is required for IL-2-induced cell cycle progression of peripheral T cells. , 1999, Immunity.

[12]  M. Kaplan,et al.  A Signal Transducer and Activator of  Transcription (Stat)4-independent Pathway for the Development of  T Helper Type 1 Cells , 1998, The Journal of experimental medicine.

[13]  P. Doherty,et al.  Requirement for Stat4 in interleukin-12-mediated responses of natural killer and T cells , 1996, Nature.

[14]  G. Stark,et al.  Complementation of a mutant cell line: central role of the 91 kDa polypeptide of ISGF3 in the interferon‐alpha and ‐gamma signal transduction pathways. , 1993, The EMBO journal.

[15]  S. Szabo,et al.  Interleukin 12 signaling in T helper type 1 (Th1) cells involves tyrosine phosphorylation of signal transducer and activator of transcription (Stat)3 and Stat4 , 1995, The Journal of experimental medicine.

[16]  C. Ware,et al.  Targeted disruption of the low-affinity leukemia inhibitory factor receptor gene causes placental, skeletal, neural and metabolic defects and results in perinatal death. , 1995, Development.

[17]  S. Akira,et al.  Defective IL-2-mediated IL-2 receptor alpha chain expression in Stat3-deficient T lymphocytes. , 1998, International immunology.

[18]  J. Darnell,et al.  Transcriptional induction of two genes in human cells by beta interferon. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[19]  J. Darnell,et al.  Transcriptionally active Stat1 is required for the antiproliferative effects of both interferon alpha and interferon gamma. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[20]  N. Copeland,et al.  Distribution of the mammalian Stat gene family in mouse chromosomes. , 1995, Genomics.

[21]  Michael P. Brown,et al.  Stat5a and Stat5b Proteins Have Essential and Nonessential, or Redundant, Roles in Cytokine Responses , 1998, Cell.

[22]  P. Thompson,et al.  STAT6 is required for IL-4-induced germline Ig gene transcription and switch recombination. , 1998, Journal of immunology.

[23]  M. Tymms,et al.  A null mutation in the gene encoding a type I interferon receptor component eliminates antiproliferative and antiviral responses to interferons alpha and beta and alters macrophage responses. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[24]  S. Akira,et al.  Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway , 1994, Cell.

[25]  K. Herrup,et al.  Targeted disruption of mouse EGF receptor: effect of genetic background on mutant phenotype. , 1995, Science.

[26]  G. Stark,et al.  A major role for the protein tyrosine kinase JAK1 in the JAK/STAT signal transduction pathway in response to interleukin‐6. , 1995, The EMBO journal.

[27]  B. Bloom,et al.  Interferon-gamma-induced transcriptional activation is mediated by protein kinase C. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[28]  R. Schreiber,et al.  Requirement of endogenous interferon-gamma production for resolution of Listeria monocytogenes infection. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[29]  L. Hennighausen,et al.  Stat5a is mandatory for adult mammary gland development and lactogenesis. , 1997, Genes & development.

[30]  A. García-Sastre,et al.  The Role of Interferon in Influenza Virus Tissue Tropism , 1998, Journal of Virology.

[31]  G. Stark,et al.  Molecular cloning of a gene selectively induced by gamma interferon from human macrophage cell line U937 , 1989, Molecular and cellular biology.

[32]  J. Darnell,et al.  Stat3 and Stat4: members of the family of signal transducers and activators of transcription. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[33]  J. Darnell,et al.  Interferon-dependent transcriptional activation: signal transduction without second messenger involvement? , 1990, The New biologist.

[34]  L. Staudt,et al.  T helper type 2 inflammatory disease in the absence of interleukin 4 and transcription factor STAT6. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[35]  L. Staudt,et al.  Control of inflammation, cytokine expression, and germinal center formation by BCL-6. , 1997, Science.

[36]  R. Schreiber,et al.  Targeted Disruption of the Stat1 Gene in Mice Reveals Unexpected Physiologic Specificity in the JAK–STAT Signaling Pathway , 1996, Cell.

[37]  D. Levy,et al.  FGF signaling inhibits chondrocyte proliferation and regulates bone development through the STAT-1 pathway. , 1999, Genes & development.

[38]  P. Kelly,et al.  Null mutation of the prolactin receptor gene produces multiple reproductive defects in the mouse. , 1997, Genes & development.

[39]  M Aguet,et al.  Functional role of type I and type II interferons in antiviral defense. , 1994, Science.

[40]  J. Darnell,et al.  Activation of transcription by IFN-gamma: tyrosine phosphorylation of a 91-kD DNA binding protein. , 1992, Science.

[41]  M. Kaplan,et al.  Stat Proteins Control Lymphocyte Proliferation by Regulating p27Kip1 Expression , 1998, Molecular and Cellular Biology.

[42]  D. Levy,et al.  Acute phase response factor and additional members of the interferon-stimulated gene factor 3 family integrate diverse signals from cytokines, interferons, and growth factors. , 1994, The Journal of biological chemistry.

[43]  N. Copeland,et al.  Stat4, a novel gamma interferon activation site-binding protein expressed in early myeloid differentiation , 1994, Molecular and cellular biology.

[44]  G. Stark,et al.  Transcriptional and posttranscriptional regulation of interferon-induced gene expression in human cells , 1984, Cell.

[45]  S. Akira,et al.  Abrogation of Bronchial Eosinophilic Inflammation and Airway Hyperreactivity in Signal Transducers and Activators of Transcription (STAT)6-deficient Mice , 1998, The Journal of experimental medicine.

[46]  W. Leonard,et al.  An indirect effect of Stat5a in IL-2-induced proliferation: a critical role for Stat5a in IL-2-mediated IL-2 receptor alpha chain induction. , 1997, Immunity.

[47]  E. Wagner,et al.  Strain-dependent epithelial defects in mice lacking the EGF receptor. , 1995, Science.

[48]  S. Akira,et al.  STAT3 activation is a critical step in gp130-mediated terminal differentiation and growth arrest of a myeloid cell line. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[49]  M. Wills-Karp,et al.  Signal Transducer and Activator of Transcription Factor 6 (Stat6)-deficient Mice Are Protected from Antigen-induced Airway Hyperresponsiveness and Mucus Production , 1998, The Journal of experimental medicine.

[50]  P. Pandolfi,et al.  The BCL-6 proto-oncogene controls germinal-centre formation and Th2-type inflammation , 1997, Nature Genetics.

[51]  D. Waxman,et al.  Growth hormone regulation of male-specific rat liver P450s 2A2 and 3A2: induction by intermittent growth hormone pulses in male but not female rats rendered growth hormone deficient by neonatal monosodium glutamate. , 1995, Molecular pharmacology.

[52]  J. Darnell,et al.  STAT signaling is active during early mammalian development , 1997, Developmental dynamics : an official publication of the American Association of Anatomists.

[53]  S. Akira,et al.  Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[54]  R. Schreiber,et al.  Demonstration of an interferon γ-dependent tumor surveillance system in immunocompetent mice , 1998 .

[55]  Xin-Yuan Fu,et al.  Activation of Statl by mutant fibroblast growth-factor receptor in thanatophoric dysplasia type II dwarfism , 1997, Nature.

[56]  J. Lammers,et al.  STAT3β, a Splice Variant of Transcription Factor STAT3, Is a Dominant Negative Regulator of Transcription* , 1996, The Journal of Biological Chemistry.

[57]  M. Kaplan,et al.  Stat6 is required for mediating responses to IL-4 and for development of Th2 cells. , 1996, Immunity.

[58]  B. Groner,et al.  Mammary gland factor (MGF) is a novel member of the cytokine regulated transcription factor gene family and confers the prolactin response. , 1994, The EMBO journal.

[59]  T. Hirano,et al.  A central role for Stat3 in IL‐6‐induced regulation of growth and differentiation in M1 leukemia cells. , 1996, The EMBO journal.

[60]  B Swolin,et al.  Mice deficient for PDGF B show renal, cardiovascular, and hematological abnormalities. , 1994, Genes & development.

[61]  J. Turkson,et al.  Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells. , 1999, Immunity.

[62]  M. Kaplan,et al.  Th2 cells are required for the Schistosoma mansoni egg-induced granulomatous response. , 1998, Journal of immunology.

[63]  S. Akira,et al.  Enhanced Th1 activity and development of chronic enterocolitis in mice devoid of Stat3 in macrophages and neutrophils. , 1999, Immunity.

[64]  W. Leonard,et al.  Stat5b Is Essential for Natural Killer Cell–mediated Proliferation and Cytolytic Activity , 1998, The Journal of experimental medicine.

[65]  S. Akira,et al.  Essential role of Stat6 in IL-4 signalling , 1996, Nature.

[66]  W. Paul,et al.  Lack of IL-4-induced Th2 response and IgE class switching in mice with disrupted State6 gene , 1996, Nature.

[67]  K. Murphy,et al.  Lineage-specific Requirement for Signal Transducer and Activator of  Transcription (Stat)4 in Interferon γ Production from CD4+ Versus CD8+ T Cells , 1999, The Journal of experimental medicine.