GSBS Student Publications

Title

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

GSBS Program

Biochemistry & Molecular Pharmacology

UMMS Affiliation

Department of Molecular Genetics and Microbiology

Date

8-1-1995

Document Type

Article

Medical Subject Headings

Animals; Base Sequence; Cyclic AMP Response Element-Binding Protein; DNA Footprinting; DNA-Binding Proteins; Dexamethasone; Forskolin; Fos-Related Antigen-2; Gene Expression Regulation; Genes, jun; Molecular Sequence Data; Neurotensin; Oligodeoxyribonucleotides; PC12 Cells; Peptide Fragments; Proto-Oncogene Proteins c-fos; Proto-Oncogene Proteins c-jun; Rats; Receptors, Glucocorticoid; Regulatory Sequences, Nucleic Acid; Signal Transduction; Transcription Factor AP-1; Transcription Factors

Disciplines

Life Sciences | Medicine and Health Sciences

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.

Rights and Permissions

Citation: Mol Endocrinol. 1995 Aug;9(8):981-93.

Related Resources

Link to article in PubMed

Journal Title

Molecular endocrinology (Baltimore, Md.)

PubMed ID

7476995