Transforming Growth Factor-β and Ciliary Neurotrophic Factor Synergistically Induce Vasoactive Intestinal Peptide Gene Expression through the Cooperation of Smad, STAT, and AP-1 Sites

• Published in: The Journal of biological chemistry Vol. 276; no. 23; p. 19966
• Main Authors: Richard L. Pitts, Shuibang Wang, Elizabeth A. Jones, Aviva J. Symes
• Format: Journal Article
• Language: English
• Published: American Society for Biochemistry and Molecular Biology 08-06-2001
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M011759200

The cytokine ciliary neurotrophic factor (CNTF) and transforming growth factor-β (TGF-β) both induce transcription of the
vasoactive intestinal peptide (VIP) gene through a 180-base pair cytokine response element (CyRE) in the VIP promoter. While
CNTF induces STAT and AP-1 proteins to bind to cognate sites in the VIP CyRE, the mechanism through which TGF-β acts to induce
VIP gene transcription is not known. Here we show that Smad3 and Smad4 proteins can bind to two distinct sites within the
VIP CyRE. These sites are absolutely required for the induction of VIP CyRE transcription by TGF-β. TGF-β induces endogenous
Smad-containing complexes to bind to these sites in human neuroblastoma cells. CNTF and TGF-β synergize to induce VIP mRNA
expression and transcription through the VIP CyRE. This synergy is dependent on the Smad, STAT, and AP-1 sites, suggesting
that these two independent cytokine pathways synergize through the cooperation of pathway-specific transcription factors binding
to distinct sites within the VIP CyRE.