Synergistic activation of neurotensin/neuromedin N gene expression by c-Jun and glucocorticoids: novel effects of Fos family proteins.
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.
D000818:Animals; D001483:Base Sequence; D005576:Colforsin / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D018983:DNA Footprinting; D004268:DNA-Binding Proteins / Q000502:physiology; D003907:Dexamethasone / Q000494:pharmacology; D051921:Fos-Related Antigen-2; D005786:Gene Expression Regulation; D016758:Genes, jun; D008969:Molecular Sequence Data; D009496:Neurotensin / Q000235:genetics*; D009838:Oligodeoxyribonucleotides / Q000737:chemistry; D016716:PC12 Cells; D010446:Peptide Fragments / Q000235:genetics*; D016760:Proto-Oncogene Proteins c-fos / Q000502:physiology; D016755:Proto-Oncogene Proteins c-jun / Q000502:physiology*; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000502:physiology; D012045:Regulatory Sequences, Nucleic Acid; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology; D015533:Transcriptional Activation; D000099169:Fos-Related Antigen 1
D005576:Colforsin; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D003907:Dexamethasone; D051921:Fos-Related Antigen-2; D009496:Neurotensin; D009838:Oligodeoxyribonucleotides; D010446:Peptide Fragments; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D011965:Receptors, Glucocorticoid; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D000099169:Fos-Related Antigen 1; C497874:Fosl2 protein, rat; C042090:neuromedin N