Molecular Endocrinology, Vol 8, 1750-1763, Copyright © 1994 by Endocrine Society

ARTICLES

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

A Symes, S Lewis, L Corpus, P Rajan, SE Hyman and JS Fink
Department of Neurology, Massachusetts General Hospital, Boston 02114.

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.

This article has been cited by other articles:

				S.-W. M. Koh, J. Celeste, and C. Y. P. Ku Functional CNTF Receptor {alpha} Subunit Restored by Its Recombinant in Corneal Endothelial Cells in Stored Human Donor Corneas: Connexin-43 Upregulation Invest. Ophthalmol. Vis. Sci., April 1, 2009; 50(4): 1801 - 1807. [Abstract] [Full Text] [PDF]

				S. Dziennis and B. A. Habecker Cytokine Suppression of Dopamine-beta -hydroxylase by Extracellular Signal-regulated Kinase-dependent and -independent Pathways J. Biol. Chem., April 25, 2003; 278(18): 15897 - 15904. [Abstract] [Full Text] [PDF]

				S.-W. M. Koh Ciliary Neurotrophic Factor Released by Corneal Endothelium Surviving Oxidative Stress Ex Vivo Invest. Ophthalmol. Vis. Sci., September 1, 2002; 43(9): 2887 - 2896. [Abstract] [Full Text] [PDF]

				A. J. Symes, R. L. Pitts, J. Conover, K. Kos, and J. Coulombe Synergy of Activin and Ciliary Neurotrophic Factor Signaling Pathways in the Induction of Vasoactive Intestinal Peptide Gene Expression Mol. Endocrinol., March 1, 2000; 14(3): 429 - 439. [Abstract] [Full Text]

				X. Zhang, M. H. Wrzeszczynska, C. M. Horvath, and J. E. Darnell Jr. Interacting Regions in Stat3 and c-Jun That Participate in Cooperative Transcriptional Activation Mol. Cell. Biol., October 1, 1999; 19(10): 7138 - 7146. [Abstract] [Full Text] [PDF]

				S. H. Hahm and L. E. Eiden Two Separate Cis-active Elements of the Vasoactive Intestinal Peptide Gene Mediate Constitutive and Inducible Transcription by Binding Different Sets of AP-1 Proteins J. Biol. Chem., September 3, 1999; 274(36): 25588 - 25593. [Abstract] [Full Text] [PDF]

				J. Ramdas and J. M. Harmon Glucocorticoid-Induced Apoptosis and Regulation of NF-{kappa}B Activity in Human Leukemic T Cells Endocrinology, September 1, 1998; 139(9): 3813 - 3821. [Abstract] [Full Text] [PDF]

				R. P. Mohney and R. E. Zigmond Vasoactive Intestinal Peptide Enhances Its Own Expression in Sympathetic Neurons after Injury J. Neurosci., July 15, 1998; 18(14): 5285 - 5293. [Abstract] [Full Text] [PDF]

				S. H. Hahm and L. E. Eiden Five Discrete Cis-active Domains Direct Cell Type-specific Transcription of the Vasoactive Intestinal Peptide (VIP) Gene J. Biol. Chem., July 3, 1998; 273(27): 17086 - 17094. [Abstract] [Full Text] [PDF]

				L. R. Carpenter, T. J. Farruggella, A. Symes, M. L. Karow, G. D. Yancopoulos, and N. Stahl Enhancing leptin response by preventing SH2-containing phosphatase 2 interaction with Ob receptor PNAS, May 26, 1998; 95(11): 6061 - 6066. [Abstract] [Full Text] [PDF]

				P. Rajan and R. D. G. McKay Multiple Routes to Astrocytic Differentiation in the CNS J. Neurosci., May 15, 1998; 18(10): 3620 - 3629. [Abstract] [Full Text] [PDF]

				T. Servidei, Y. Aoki, S. E. Lewis, A. Symes, J. S. Fink, and S. A. Reeves Coordinate Regulation of STAT Signaling and c-fos Expression by the Tyrosine Phosphatase SHP-2 J. Biol. Chem., March 13, 1998; 273(11): 6233 - 6241. [Abstract] [Full Text] [PDF]

				U. Vinkemeier, I. Moarefi, J. E. Darnell Jr., and J. Kuriyan Structure of the Amino-Terminal Protein Interaction Domain of STAT-4 Science, February 13, 1998; 279(5353): 1048 - 1052. [Abstract] [Full Text]

				B. A. Habecker, A. J. Symes, N. Stahl, N. J. Francis, A. Economides, J. S. Fink, G. D. Yancopoulos, and S. C. Landis A Sweat Gland-derived Differentiation Activity Acts through Known Cytokine Signaling Pathways J. Biol. Chem., November 28, 1997; 272(48): 30421 - 30428. [Abstract] [Full Text] [PDF]

				A. B. Vernallis, K. R. Hudson, and J. K. Heath An Antagonist for the Leukemia Inhibitory Factor Receptor Inhibits Leukemia Inhibitory Factor, Cardiotrophin-1, Ciliary Neurotrophic Factor, and Oncostatin M J. Biol. Chem., October 24, 1997; 272(43): 26947 - 26952. [Abstract] [Full Text] [PDF]

				M. A. Wishingrad, S. Koshlukova, and S. W. Halvorsen Ciliary Neurotrophic Factor Stimulates the Phosphorylation of Two Forms of STAT3 in Chick Ciliary Ganglion Neurons J. Biol. Chem., August 8, 1997; 272(32): 19752 - 19757. [Abstract] [Full Text] [PDF]

				W. P. Schiemann, J. L. Bartoe, and N. M. Nathanson Box 3-independent Signaling Mechanisms Are Involved in Leukemia Inhibitory Factor Receptor alpha - and gp130-mediated Stimulation of Mitogen-activated Protein Kinase. EVIDENCE FOR PARTICIPATION OF MULTIPLE SIGNALING PATHWAYS WHICH CONVERGE AT Ras J. Biol. Chem., June 27, 1997; 272(26): 16631 - 16636. [Abstract] [Full Text] [PDF]

				A. Symes, T. Gearan, J. Eby, and J. S. Fink Integration of Jak-Stat and AP-1 Signaling Pathways at the Vasoactive Intestinal Peptide Cytokine Response Element Regulates Ciliary Neurotrophic Factor-dependent Transcription J. Biol. Chem., April 11, 1997; 272(15): 9648 - 9654. [Abstract] [Full Text] [PDF]

				M. T. Berhow, N. Hiroi, L. A. Kobierski, S. E. Hyman, and E. J. Nestler Influence of Cocaine on the JAK-STAT Pathway in the Mesolimbic Dopamine System J. Neurosci., December 15, 1996; 16(24): 8019 - 8026. [Abstract] [Full Text] [PDF]

				E. A. Jones, J. Conover, and A. J. Symes Identification of a Novel gp130-responsive Site in the Vasoactive Intestinal Peptide Cytokine Response Element J. Biol. Chem., November 10, 2000; 275(46): 36013 - 36020. [Abstract] [Full Text] [PDF]

				R. L. Pitts, S. Wang, E. A. Jones, and A. J. Symes Transforming Growth Factor-beta and Ciliary Neurotrophic Factor Synergistically Induce Vasoactive Intestinal Peptide Gene Expression through the Cooperation of Smad, STAT, and AP-1 Sites J. Biol. Chem., June 1, 2001; 276(23): 19966 - 19973. [Abstract] [Full Text] [PDF]