Synergistic activation of neurotensin/neuromedin N gene expression by c-Jun and glucocorticoids: novel effects of Fos family proteins

Mol Endocrinol. 1995 Aug;9(8):981-93. doi: 10.1210/mend.9.8.7476995.

Abstract

The cis-regulatory region of the neurotensin/neuromedin N (NT/N) gene integrates diverse environmental signals in the neuroendocrine PC12 cell line, resulting in remarkable synergistic regulation. An AP-1 site appears to play a pivotal role in cooperative NT/N gene activation, as mutations in this site decrease responses to all inducer combinations by at least an order of magnitude. Here we report that c-Jun acts synergistically with glucocorticoids to activate the NT/N promoter, and that Fos family proteins have novel regulatory effects on this interaction. Cotransfection of individual pCMV-AP-1 expression plasmids revealed that c-Jun most potently activates the NT/N promoter and that costimulation with dexamethasone results in a further 6- to 12-fold increase in expression. Unlike its general inhibitory effects on glucocorticoid regulation in other systems, c-Fos potentiated activation by glucocorticoids when coexpressed with c-Jun, and Fos B had a similar, but more limited, positive effect. In contrast, Fra-1 reversed the direction of glucocorticoid regulation, and Fra-2 abolished synergism. AP-1, cAMP response element, and glucocorticoid response element motifs are required for full cooperative activation by either c-Jun or c-Jun/c-Fos and glucocorticoids. These results indicate that NT/N promoter activation involves synergistic interactions between specific AP-1 complexes and ligand-activated glucocorticoid receptor, and similar mechanisms may regulate NT/N gene expression in central neurons.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Base Sequence
  • Colforsin / pharmacology
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • DNA Footprinting
  • DNA-Binding Proteins / physiology
  • Dexamethasone / pharmacology
  • Fos-Related Antigen-2
  • Gene Expression Regulation
  • Genes, jun
  • Molecular Sequence Data
  • Neurotensin / genetics*
  • Oligodeoxyribonucleotides / chemistry
  • PC12 Cells
  • Peptide Fragments / genetics*
  • Proto-Oncogene Proteins c-fos / physiology
  • Proto-Oncogene Proteins c-jun / physiology*
  • Rats
  • Receptors, Glucocorticoid / physiology
  • Regulatory Sequences, Nucleic Acid
  • Signal Transduction
  • Transcription Factor AP-1 / physiology*
  • Transcription Factors / physiology
  • Transcriptional Activation

Substances

  • Cyclic AMP Response Element-Binding Protein
  • DNA-Binding Proteins
  • Fos-Related Antigen-2
  • Fosl2 protein, rat
  • Oligodeoxyribonucleotides
  • Peptide Fragments
  • Proto-Oncogene Proteins c-fos
  • Proto-Oncogene Proteins c-jun
  • Receptors, Glucocorticoid
  • Transcription Factor AP-1
  • Transcription Factors
  • fos-related antigen 1
  • neuromedin N
  • Colforsin
  • Neurotensin
  • Dexamethasone