Activation of Signal Transducers and Activators of Transcription 1 and 3 by Leukemia Inhibitory Factor, Oncostatin-M, and Interferon-γ in Adipocytes*

We have recently demonstrated that signal transducers and activators of transcription (STATs) 1, 3, 5A, 5B, and 6 are expressed in both cultured and native adipocytes. Our current studies have focused on the activation of STATs 1 and 3 by leukemia inhibitory factor (LIF), oncostatin-M (OSM), and interferon-γ (IFNγ) in 3T3-L1 adipocytes. IFNγ is shown to be a potent activator of STAT 1 as indicated by both tyrosine phosphorylation and nuclear translocation. However, LIF and OSM, which are potent inducers of STAT 3, are less potent activators of STAT 1 as measured by both tyrosine phosphorylation and nuclear translocation. Both STATs 1 and 3 were translocated to the nucleus in a time-dependent fashion following LIF treatment. In addition, IFNγ resulted in a time- and dose-dependent effect on STATs 1 and 3 nuclear translocation. Growth hormone, a potent activator of STATs 5A and 5B, had a minimal effect on STAT 1 and STAT 3 tyrosine phosphorylation. Preincubation with either insulin or growth hormone had no detectable effects on the tyrosine phosphorylation or nuclear translocation of STATs 1 and 3 induced by LIF, OSM, or IFNγ. The effects of LIF and IFNγ on STAT 1 and 3 tyrosine phosphorylation and nuclear translocation were confirmed in native rat adipocytes. In 3T3-L1 adipocytes, a low level of serine phosphorylation of STAT 3 on residue 727 was observed and was markedly enhanced by insulin, LIF, or OSM. This increase in STAT 3 Ser727 phosphorylation was dependent upon the activation of MAPK, since the MAPK kinase inhibitor (PD98059) reduced STAT 3 Ser727 phosphorylation to basal levels. The inhibition of MAPK had no effect on the ability of STATs 1 and 3 to be tyrosine-phosphorylated or translocate to the nucleus. These studies demonstrate the highly specific and quantitative activation of STATs 1 and 3 by LIF, OSM, and IFNγ in adipocytes and indicate that STAT 3 is a substrate for MAPK in adipocytes.

[1]  J. Balhoff,et al.  Highly specific and quantitative activation of STATs in 3T3-L1 adipocytes. , 1998, Biochemical and biophysical research communications.

[2]  A. Arıcı,et al.  Leukemia Inhibitory Factor in Human Reproduction , 1998, American journal of reproductive immunology.

[3]  J. Ritz,et al.  B lymphocytes from patients with chronic lymphocytic leukemia contain signal transducer and activator of transcription (STAT) 1 and STAT3 constitutively phosphorylated on serine residues. , 1997, The Journal of clinical investigation.

[4]  J. Blenis,et al.  STAT3 serine phosphorylation by ERK-dependent and -independent pathways negatively modulates its tyrosine phosphorylation , 1997, Molecular and cellular biology.

[5]  Fabienne De Graeve,et al.  Leukemia Inhibitory Factor–dependent Transcriptional Activation in Embryonic Stem Cells , 1997, The Journal of cell biology.

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

[7]  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.

[8]  E. Petricoin,et al.  Beta interferon and oncostatin M activate Raf-1 and mitogen-activated protein kinase through a JAK1-dependent pathway , 1997, Molecular and cellular biology.

[9]  C. Guillet,et al.  Signaling of Type II Oncostatin M Receptor* , 1997, The Journal of Biological Chemistry.

[10]  K. Kuropatwinski,et al.  Influence of Subunit Combinations on Signaling by Receptors for Oncostatin M, Leukemia Inhibitory Factor, and Interleukin-6* , 1997, The Journal of Biological Chemistry.

[11]  J. Darnell,et al.  Mapping of Stat3 serine phosphorylation to a single residue (727) and evidence that serine phosphorylation has no influence on DNA binding of Stat1 and Stat3. , 1997, Nucleic acids research.

[12]  B. Groner,et al.  Lactogenic Hormone Activation of Stat5 and Transcription of the β-Casein Gene in Mammary Epithelial Cells Is Independent of p42 ERK2 Mitogen-activated Protein Kinase Activity* , 1996, The Journal of Biological Chemistry.

[13]  T. Decker,et al.  Activation of different Stat5 isoforms contributes to cell-type-restricted signaling in response to interferons , 1996, Molecular and cellular biology.

[14]  H. Baumann,et al.  Insulin Modulates STAT3 Protein Activation and Gene Transcription in Hepatic Cells* , 1996, The Journal of Biological Chemistry.

[15]  D. Faller,et al.  Down-regulation of Platelet-derived Growth Factor Receptor Expression during Terminal Differentiation of 3T3-L1 Pre-adipocyte Fibroblasts* , 1996, The Journal of Biological Chemistry.

[16]  J. Pessin,et al.  Insulin Stimulates the Serine Phosphorylation of the Signal Transducer and Activator of Transcription (STAT3) Isoform (*) , 1996, The Journal of Biological Chemistry.

[17]  Alan Wells,et al.  STAT Activation by Epidermal Growth Factor (EGF) and Amphiregulin , 1996, The Journal of Biological Chemistry.

[18]  D. Ray,et al.  Leukemia inhibitory factor (LIF) stimulates proopiomelanocortin (POMC) expression in a corticotroph cell line. Role of STAT pathway. , 1996, The Journal of clinical investigation.

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

[20]  D. Cantrell,et al.  Interleukin‐2 activation of STAT5 requires the convergent action of tyrosine kinases and a serine/threonine kinase pathway distinct from the Raf1/ERK2 MAP kinase pathway. , 1996, The EMBO journal.

[21]  N. Copeland,et al.  Mouse oncostatin M: an immediate early gene induced by multiple cytokines through the JAK‐STAT5 pathway. , 1996, The EMBO journal.

[22]  M. Brizzi,et al.  Granulocyte-Macrophage Colony-stimulating Factor Stimulates JAK2 Signaling Pathway and Rapidly Activates p93, STAT1 p91, and STAT3 p92 in Polymorphonuclear Leukocytes (*) , 1996, The Journal of Biological Chemistry.

[23]  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.

[24]  E. Petricoin,et al.  Requirement for MAP kinase (ERK2) activity in interferon alpha- and interferon beta-stimulated gene expression through STAT proteins. , 1995, Science.

[25]  J. Ihle,et al.  Phosphorylation and Activation of the DNA Binding Activity of Purified Stat1 by the Janus Protein-tyrosine Kinases and the Epidermal Growth Factor Receptor (*) , 1995, The Journal of Biological Chemistry.

[26]  J. Darnell,et al.  Maximal activation of transcription by statl and stat3 requires both tyrosine and serine phosphorylation , 1995, Cell.

[27]  J. Blenis,et al.  Requirement of serine phosphorylation for formation of STAT-promoter complexes. , 1995, Science.

[28]  K. Feingold,et al.  Cytokines induce catabolic effects in cultured adipocytes by multiple mechanisms. , 1994, Cytokine.

[29]  D. Fraker,et al.  Characterization of differentiation factor/leukaemia inhibitory factor effect on lipoprotein lipase activity and mRNA in 3T3-L1 adipocytes. , 1994, Cytokine.

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

[31]  S. Dower,et al.  Oncostatin M and leukemia inhibitory factor trigger overlapping and different signals through partially shared receptor complexes. , 1994, The Journal of biological chemistry.

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

[33]  R. Aebersold,et al.  Proteins of transcription factor ISGF-3: one gene encodes the 91-and 84-kDa ISGF-3 proteins that are activated by interferon alpha. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[34]  C. Remacle,et al.  Interferon‐γ and interleukin‐1β inhibit adipoconversion in cultured rodent preadipocytes , 1992, Journal of cellular physiology.

[35]  T. Rose,et al.  Oncostatin M is a member of a cytokine family that includes leukemia-inhibitory factor, granulocyte colony-stimulating factor, and interleukin 6. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[36]  U. K. Laemmli,et al.  Cleavage of Structural Proteins during the Assembly of the Head of Bacteriophage T4 , 1970, Nature.

[37]  M. Rodbell.  METABOLISM OF ISOLATED FAT CELLS. I. EFFECTS OF HORMONES ON GLUCOSE METABOLISM AND LIPOLYSIS. , 1964, The Journal of biological chemistry.