STAT proteins participate in the regulation of the vasoactive intestinal peptide gene by the ciliary neurotrophic factor family of cytokines.

Ciliary neurotrophic factor (CNTF) and leukemia inhibitory factor (LIF) are members of a family of neuropoietic cytokines that have a broad range of actions on many different neuronal populations. In cultured sympathetic neurons, CNTF and LIF induce transcription of the VIP and other neuropeptide genes as part of a program of differentiation. To gain insight into the nuclear events involved in cytokine-mediated activation of the neuropeptide genes involved in neuronal differentiation, we have investigated the mechanisms of transcriptional activation of the vasoactive intestinal peptide (VIP) gene by the CNTF family of cytokines. In the neuroblastoma cell line NBFL, CNTF, LIF, and a related cytokine, oncostatin-M, activate VIP gene transcription through a 180-base pair cytokine response element (CyRE). Deletion analysis of the VIP CyRE showed that multiple regions within the 180 base-pairs are important for cytokine-mediated transcriptional activation of the VIP gene. To one of these regions within the CyRE, cytokine treatment induces binding of a protein complex composed of members of the signal transducers and activators of transcription (STAT) transcription factor family. Mutation of this STAT-binding site attenuates cytokine-mediated transcriptional activation. LIF treatment of primary sympathetic neurons also induced binding of a STAT-containing protein complex to the VIP CyRE. Thus, activation of STAT transcription factors contributes to the induction of the VIp gene by the CNTF family of cytokines and may be involved in cytokine-mediated differentiation of sympathetic neurons.

[1]  S. Hyman,et al.  Leukemia Inhibitory Factor and Ciliary Neurotrophic Factor Increase Activated Ras in a Neuroblastoma Cell Line and in Sympathetic Neuron Cultures , 1994, Journal of neurochemistry.

[2]  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.

[3]  G. Stark,et al.  Complementation by the protein tyrosine kinase JAK2 of a mutant cell line defective in the interferon-& gamma; signal transduction pathway , 1993, Nature.

[4]  Xin-Yuan Fu,et al.  Transcription factor p91 interacts with the epidermal growth factor receptor and mediates activation of the c-fos gene promoter , 1993, Cell.

[5]  S. Cohen,et al.  Induction by EGF and interferon-gamma of tyrosine phosphorylated DNA binding proteins in mouse liver nuclei. , 1993, Science.

[6]  J. Darnell,et al.  A common nuclear signal transduction pathway activated by growth factor and cytokine receptors. , 1993, Science.

[7]  J. Darnell,et al.  The genomic structure of the murine ICSBP gene reveals the presence of the gamma interferon-responsive element, to which an ISGF3 alpha subunit (or similar) molecule binds , 1993, Molecular and cellular biology.

[8]  T. Hirano,et al.  Identification of a novel interleukin-6 response element containing an Ets-binding site and a CRE-like site in the junB promoter , 1993, Molecular and cellular biology.

[9]  S. Landis,et al.  Regulation of substance P is similar to that of vasoactive intestinal peptide after axotomy or explantation of the rat superior cervical ganglion. , 1993, Journal of neurobiology.

[10]  S. Akira,et al.  Phosphorylation at threonine-235 by a ras-dependent mitogen-activated protein kinase cascade is essential for transcription factor NF-IL6. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[11]  G. Courtois,et al.  The human beta fibrinogen promoter contains a hepatocyte nuclear factor 1-dependent interleukin-6-responsive element , 1993, Molecular and cellular biology.

[12]  P. Heinrich,et al.  Acute-phase response factor, a nuclear factor binding to acute-phase response elements, is rapidly activated by interleukin-6 at the posttranslational level , 1993, Molecular and cellular biology.

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

[14]  S. Landis,et al.  Oncostatin M regulates VIP expression in a human neuroblastoma cell line. , 1992, Neuroreport.

[15]  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.

[16]  R. Aebersold,et al.  The proteins of ISGF-3, the interferon alpha-induced transcriptional activator, define a gene family involved in signal transduction. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[17]  J. Darnell,et al.  Interferon-dependent tyrosine phosphorylation of a latent cytoplasmic transcription factor. , 1992, Science.

[18]  M. Fellous,et al.  A protein tyrosine kinase in the interferon α β signaling pathway , 1992, Cell.

[19]  S. Landis,et al.  Effects of ciliary neurotrophic factor (CNTF) and depolarization on neuropeptide expression in cultured sympathetic neurons. , 1992, Developmental biology.

[20]  A. K. Hall,et al.  Cytokines and neurokines: related ligands and related receptors , 1992, Trends in Neurosciences.

[21]  S. Varon,et al.  Ciliary neurotrophic factor prevents neuronal degeneration and promotes low affinity NGF receptor expression in the adult rat CNS , 1992, Neuron.

[22]  Gearing Dp,et al.  Oncostatin M binds the high-affinity leukemia inhibitory factor receptor. , 1992 .

[23]  C. Thut,et al.  Leukemia inhibitory factor receptor is structurally related to the IL‐6 signal transducer, gp130. , 1991, The EMBO journal.

[24]  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.

[25]  J. Brugge,et al.  Leukemia inhibitory factor and interleukin-6 trigger the same immediate early response, including tyrosine phosphorylation, upon induction of myeloid leukemia differentiation , 1991, Molecular and cellular biology.

[26]  J. Bazan.  Neuropoietic cytokines in the hematopoietic fold , 1991, Neuron.

[27]  S. Nakanishi,et al.  Recombinant Cholinergic Differentiation Factor (Leukemia Inhibitory Factor) Regulates Sympathetic Neuron Phenotype by Alterations in the Size and Amounts of Neuropeptide mRNAs , 1991, Journal of neurochemistry.

[28]  D. Hilton,et al.  Leukemia inhibitory factor: A biological perspective , 1991, Journal of cellular biochemistry.

[29]  R. Wall,et al.  Interleukin-6 signals activating junB and TIS11 gene transcription in a B-cell hybridoma , 1991, Molecular and cellular biology.

[30]  P. Monaci,et al.  Synergistic trans‐activation of the human C‐reactive protein promoter by transcription factor HNF‐1 binding at two distinct sites. , 1990, The EMBO journal.

[31]  B. Cochran,et al.  The SIF binding element confers sis/PDGF inducibility onto the c‐fos promoter. , 1990, The EMBO journal.

[32]  R. Cortese,et al.  IL-6DBP, a nuclear protein involved in interleukin-6 signal transduction, defines a new family of leucine zipper proteins related to C EBP , 1990, Cell.

[33]  M. Raff,et al.  Extracellular matrix-associated molecules collaborate with ciliary neurotrophic factor to induce type-2 astrocyte development , 1990, The Journal of cell biology.

[34]  M. Carter,et al.  Structure, expression, and some regulatory mechanisms of the rat preprotachykinin gene encoding substance P, neurokinin A, neuropeptide K, and neuropeptide gamma , 1990, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[35]  S. Akira,et al.  A nuclear factor for IL‐6 expression (NF‐IL6) is a member of a C/EBP family. , 1990, The EMBO journal.

[36]  G. Ciliberto,et al.  Constitutive and IL‐6‐induced nuclear factors that interact with the human C‐reactive protein promoter. , 1990, The EMBO journal.

[37]  R. Thakker,et al.  Structure and methylation of the human calcitonin/α-CGRP gene , 1989 .

[38]  W. Schaffner,et al.  Rapid detection of octamer binding proteins with 'mini-extracts', prepared from a small number of cells. , 1989, Nucleic acids research.

[39]  R. Goodman,et al.  The CGTCA sequence motif is essential for biological activity of the vasoactive intestinal peptide gene cAMP-regulated enhancer. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[40]  M. Nishizawa,et al.  Complete Nucleotide Sequence of Human Vasoactive Intestinal Peptide/PHM‐27 Gene and Its Inducible Promoter a , 1988, Annals of the New York Academy of Sciences.

[41]  R. Goodman,et al.  Identification of a region in the human vasoactive intestinal polypeptide gene responsible for regulation by cyclic AMP. , 1987, The Journal of biological chemistry.

[42]  W. Rutter,et al.  Sequence of the human somatostatin I gene. , 1984, Science.