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PMID: 7935470 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Fibroblast growth factor and cyclic AMP (cAMP) synergistically activate gene expression at a cAMP response element.

Molecular and cellular biology ·Vol. 14 ·No. 11 ·1994-11-00 ·Pages 7546-56

Tan Y, Low KG, Boccia C, Grossman J, Comb MJ

Abstract

Growth factors and cyclic AMP (cAMP) are known to activate distinct intracellular signaling pathways. Fibroblast growth factor (FGF) activates ras-dependent kinase cascades, resulting in the activation of MAP kinases, whereas cAMP activates protein kinase A. In this study, we report that growth factors and cAMP act synergistically to stimulate proenkephalin gene expression. Positive synergy between growth factor- and cAMP-activated signaling pathways on gene expression has not been previously reported, and we suggest that these synergistic interactions represent a useful model for analyzing interactions between these pathways. Transfection and mutational studies indicate that both FGF-dependent gene activation and cAMP-dependent gene activation require cAMP response element 2 (CRE-2), a previously characterized cAMP-dependent regulatory element. Furthermore, multiple copies of this element are sufficient to confer FGF regulation upon a minimal promoter, indicating that FGF and cAMP signaling converge upon transcription factors acting at CRE-2. Among many different ATF/AP-1 factors tested, two factors, ATF-3 and c-Jun, stimulate proenkephalin transcription in an FGF- or Ras-dependent fashion. Finally, we show that ATF-3 and c-Jun form heterodimeric complexes in SK-N-MC cells and that the levels of both proteins are increased in response to FGF but not cAMP. Together, these results indicate that growth factor- and cAMP-dependent signaling pathways converge at CRE-2 to synergistically stimulate gene expression and that ATF-3 and c-Jun regulate proenkephalin transcription in response to both growth factor- and cAMP-dependent intracellular signaling pathways.

Related Genes
Ras
MeSH Terms
Activating Transcription Factor 2 Activating Transcription Factor 3 Base Sequence Cell Line Cyclic AMP/administration & dosage,metabolism,pharmacology Cyclic AMP Response Element-Binding Protein/genetics DNA Primers/genetics Drug Synergism Enkephalins/genetics Fibroblast Growth Factors/administration & dosage,pharmacology Gene Expression Regulation/drug effects Genes, ras Humans Molecular Sequence Data Protein Precursors/genetics Proto-Oncogene Proteins c-jun/metabolism Signal Transduction Transcription Factors/metabolism Transcriptional Activation Transfection
Chemicals
Activating Transcription Factor 2 Activating Transcription Factor 3 Cyclic AMP Response Element-Binding Protein DNA Primers Enkephalins Protein Precursors Proto-Oncogene Proteins c-jun Transcription Factors proenkephalin Fibroblast Growth Factors Cyclic AMP
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Tan Y
Laboratory of Molecular Neurobiology, Massachusetts General Hospital, Charlestown 02129.
Low K G
Boccia C
Grossman J
Comb M J
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/mcb.14.11.7546-7556.1994
Published
1994-11-00
Pages
7546-56
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC359291
Subset
IM
Grants
NIDA NIH HHS · DA 0151 · United States
NIDA NIH HHS · DA 05706 · United States
External Links
PubMed source DOI: 10.1128/mcb.14.11.7546-7556.1994 PMC Full Text View journal details
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