STAT family of transcription factors in cytokine-mediated biological responses.

STAT (signal transducers and activators of transcription) family, consisting of seven members, is involved in cytokine signal transduction. Biological roles of each STAT family protein have now been elucidated through studies of gene targeted mice. Stat1 knockout mice are defective in interferon-mediated functions. Stat4 and Stat6 knockout mice show defective responses to IL-12 and IL-4, respectively. Analyses of Stat5a and Stat5b knockout mice reveal important roles in prolactin-mediated mammary gland development and growth hormone-mediated induction of sexual dimorphism, respectively. Conditional knockout study of Stat3 demonstrates its critical roles in cytokine-mediated functions in several tissues, including T cells, macrophages, skin, and mammary gland.

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

[2]  R. Schreiber,et al.  Stat recruitment by tyrosine-phosphorylated cytokine receptors: an ordered reversible affinity-driven process. , 1995, Immunity.

[3]  M. Mann,et al.  SH2 Signaling in a Lower Eukaryote: A STAT Protein That Regulates Stalk Cell Differentiation in Dictyostelium , 1997, Cell.

[4]  Samir A. Shah,et al.  T Cell–mediated Pathology in Two Models of Experimental Colitis Depends Predominantly on the Interleukin 12/Signal Transducer and Activator of Transcription (Stat)-4 Pathway, but Is Not Conditional on Interferon γ Expression by T Cells , 1998, The Journal of experimental medicine.

[5]  H. Pendeville,et al.  SOCS3 Is Essential in the Regulation of Fetal Liver Erythropoiesis , 1999, Cell.

[6]  S. McKnight,et al.  Components of a Stat recognition code: evidence for two layers of molecular selectivity. , 1995, Immunity.

[7]  D. Chang,et al.  Inhibition of Stat1-mediated gene activation by PIAS1. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

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

[9]  A. Yoshimura,et al.  SOCS1 Deficiency Causes a Lymphocyte-Dependent Perinatal Lethality , 1999, Cell.

[10]  T. Taniguchi.  Cytokine signaling through nonreceptor protein tyrosine kinases. , 1995, Science.

[11]  D. Levy,et al.  Roles of JAKs in activation of STATs and stimulation of c-fos gene expression by epidermal growth factor , 1996, Molecular and cellular biology.

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

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

[14]  J. Darnell,et al.  Stat3 as an Oncogene , 1999, Cell.

[15]  A. Cowey,et al.  Blindsight in monkeys , 1995, Nature.

[16]  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.

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

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

[19]  G. Stark,et al.  Functional subdomains of STAT2 required for preassociation with the alpha interferon receptor and for signaling , 1997, Molecular and cellular biology.

[20]  M. Vignais,et al.  Platelet-derived growth factor induces phosphorylation of multiple JAK family kinases and STAT proteins , 1996, Molecular and cellular biology.

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

[22]  A. O’Garra,et al.  Cytokines induce the development of functionally heterogeneous T helper cell subsets. , 1998, Immunity.

[23]  H. Lodish,et al.  Fetal Anemia and Apoptosis of Red Cell Progenitors in Stat5a−/−5b−/− Mice A Direct Role for Stat5 in Bcl-XL Induction , 1999, Cell.

[24]  M. Kubo,et al.  Suppression of STAT5 Functions in Liver, Mammary Glands, and T Cells in Cytokine-Inducible SH2-Containing Protein 1 Transgenic Mice , 1999, Molecular and Cellular Biology.

[25]  N. Danial,et al.  Jak-STAT signaling induced by the v-abl oncogene. , 1995, Science.

[26]  P Jay,et al.  Specific inhibition of Stat3 signal transduction by PIAS3. , 1997, Science.

[27]  W. Leonard,et al.  Constitutively activated Jak-STAT pathway in T cells transformed with HTLV-I. , 1995, Science.

[28]  Tom Maniatis,et al.  Regulation of Interferon-γ-Activated STAT1 by the Ubiquitin-Proteasome Pathway , 1996, Science.

[29]  J. Turkson,et al.  Stat3 Activation by Src Induces Specific Gene Regulation and Is Required for Cell Transformation , 1998, Molecular and Cellular Biology.

[30]  S. Bhattacharya,et al.  Cooperation of Stat2 and p300/CBP in signalling induced by interferon-α , 1996, Nature.

[31]  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.

[32]  R. Jove,et al.  Activation of STAT transcription factors in oncogenic tyrosine kinase signaling. , 1998, Journal of biomedical science.

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

[34]  S. McKnight,et al.  An interleukin-4-induced transcription factor: IL-4 Stat. , 1994, Science.

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

[36]  T. Hirano,et al.  An alternative pathway for STAT activation that is mediated by the direct interaction between JAK and STAT , 1997, Oncogene.

[37]  J. Darnell,et al.  Two contact regions between Stat1 and CBP/p300 in interferon γ signaling , 1996 .

[38]  A. Wilks,et al.  Colony-stimulating factor 1-induced STAT1 and STAT3 activation is accompanied by phosphorylation of Tyk2 in macrophages and Tyk2 and JAK1 in fibroblasts. , 1995, Blood.

[39]  P. Nowell,et al.  Activation of Jak/STAT proteins involved in signal transduction pathway mediated by receptor for interleukin 2 in malignant T lymphocytes derived from cutaneous anaplastic large T-cell lymphoma and Sezary syndrome. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[40]  Claude Desplan,et al.  Identification of a Stat Gene That Functions in Drosophila Development , 1996, Cell.

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

[42]  S. Akira,et al.  Kupffer cells from Schistosoma mansoni-infected mice participate in the prompt type 2 differentiation of hepatic T cells in response to worm antigens. , 1999, Journal of immunology.

[43]  Y. Tan,et al.  Activation and association of Stat3 with Src in v-Src-transformed cell lines , 1996, Molecular and cellular biology.

[44]  Paul J Hertzog,et al.  SOCS1 Is a Critical Inhibitor of Interferon γ Signaling and Prevents the Potentially Fatal Neonatal Actions of this Cytokine , 1999, Cell.

[45]  A. Bardelli,et al.  Induction of epithelial tubules by growth factor HGF depends on the STAT pathway , 1998, Nature.

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

[47]  Y. Uchiyama,et al.  Accelerated apoptosis of lymphocytes by augmented induction of Bax in SSI-1 (STAT-induced STAT inhibitor-1) deficient mice. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[48]  S. Akira,et al.  Suppression of epithelial apoptosis and delayed mammary gland involution in mice with a conditional knockout of Stat3. , 1999, Genes & development.

[49]  J. Ihle.  STATs: Signal Transducers and Activators of Transcription , 1996, Cell.

[50]  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.

[51]  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.

[52]  J. Girard,et al.  Identification and Localization of a Skeletal Muscle Secrotonin 5-HT2A Receptor Coupled to the Jak/STAT Pathway* , 1997, The Journal of Biological Chemistry.

[53]  J. Darnell,et al.  Transcriptional responses to polypeptide ligands: the JAK-STAT pathway. , 1995, Annual review of biochemistry.

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

[55]  T. Waldmann,et al.  Proliferation of adult T cell leukemia/lymphoma cells is associated with the constitutive activation of JAK/STAT proteins. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[56]  J. Darnell,et al.  A STAT protein domain that determines DNA sequence recognition suggests a novel DNA-binding domain. , 1995, Genes & development.

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

[58]  B. Groner,et al.  STAT-related transcription factors are constitutively activated in peripheral blood cells from acute leukemia patients , 1996 .

[59]  J. Darnell,et al.  The rapid inactivation of nuclear tyrosine phosphorylated Stat1 depends upon a protein tyrosine phosphatase. , 1996, The EMBO journal.

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

[61]  S. Akira,et al.  Cytokine signal transduction , 1994, Cell.

[62]  S. Akira,et al.  Impaired IL-13-mediated functions of macrophages in STAT6-deficient mice. , 1996, Journal of immunology.

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

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

[65]  C. Glass,et al.  Nuclear integration of JAK/STAT and Ras/AP-1 signaling by CBP and p300. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[66]  W. Leonard,et al.  Distinct tumorigenic potential of abl and raf in B cell neoplasia: abl activates the IL-6 signaling pathway. , 1996, Immunity.

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

[68]  K. Miyazono,et al.  Synergistic signaling in fetal brain by STAT3-Smad1 complex bridged by p300. , 1999, Science.

[69]  F. Kafatos,et al.  Anopheles gambiae Ag‐STAT, a new insect member of the STAT family, is activated in response to bacterial infection , 1999, The EMBO journal.

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

[71]  Norbert Perrimon,et al.  marelle Acts Downstream of the Drosophila HOP/JAK Kinase and Encodes a Protein Similar to the Mammalian STATs , 1996, Cell.

[72]  W. Leonard,et al.  The role of shared receptor motifs and common Stat proteins in the generation of cytokine pleiotropy and redundancy by IL-2, IL-4, IL-7, IL-13, and IL-15. , 1995, Immunity.

[73]  R. Jove,et al.  Enhanced DNA-binding activity of a Stat3-related protein in cells transformed by the Src oncoprotein. , 1995, Science.

[74]  Akira,et al.  STAT6 deficiency in a mouse model of allergen‐induced airways inflammation abolishes eosinophilia but induces infiltration of CD8+ T cells , 1999, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

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

[76]  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.

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

[78]  O. Silvennoinen,et al.  Signaling through the hematopoietic cytokine receptors. , 1995, Annual review of immunology.

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

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

[81]  S. Akira,et al.  Keratinocyte‐specific ablation of Stat3 exhibits impaired skin remodeling, but does not affect skin morphogenesis , 1999, The EMBO journal.