Pituitary adenyl cyclase-activating peptide: a hypophysiotropic factor that stimulates proopiomelanocortin gene transcription, and proopiomelanocortin-derived peptide secretion in corticotropic cells.
The biological effects of pituitary adenylate cyclase-activating peptide (PACAP) 27 and 38 on peptide secretion and gene regulation were studied in the mouse corticotrope-derived cell line AtT20. Treatment of these cells with PACAP 27/38 led to a dose-dependent increase in cAMP content and ACTH accumulation in the medium with an apparent ED50 value close to 10(-9) M. The genomic effects of PACAP were first investigated by using a reporter gene containing a cAMP responsive element (CRE: TGACGTCA) PACAP 27/38 stimulate transcription from this construction and the effect is further increased when cells are cotreated with the phosphodiesterase inhibitor rolipram. Furthermore, we show by measuring nuclear heterologous proopiomelanocortin (POMC) RNA levels or by using a reporter gene containing the POMC promoter region, that PACAP stimulates POMC transcription. This transcriptional stimulation is mediated by the cAMP-dependent protein kinase (PKA) since genetic inactivation of PKA by a dominant inhibitory mutant of this enzyme completely abolished the effect of PACAP on POMC transcription. Finally, we show that the transcriptional stimulation of POMC by PACAP is repressed by the glucocorticoid receptor agonist dexamethasone. Taken together, these data suggest that PACAP is a hypophysiotropic hormone that exert similar if not identical functions as corticotropin-releasing hormone (CRH) on corticotrope cells.
Institut de Physiologie et de Chimie Biologie, URA 1446 CNRS Neurophysiologie et Neurobiologie des Systèmes Endocrines, Strasbourg, France.
A L
AL
Boutillier
D
D
Monnier
B
B
Koch
J P
JP
Loeffler
D000324:Adrenocorticotropic Hormone / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics; D000242:Cyclic AMP / Q000378:metabolism / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D051379:Mice; D009479:Neuropeptides / Q000494:pharmacology*; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D010911:Pituitary Neoplasms; D011333:Pro-Opiomelanocortin / Q000235:genetics* / Q000378:metabolism*; D011993:Recombinant Fusion Proteins; D012045:Regulatory Sequences, Nucleic Acid; D013004:Somatostatin / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects*; D014407:Tumor Cells, Cultured
C495402:Adcyap1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D009479:Neuropeptides; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D011993:Recombinant Fusion Proteins; D013004:Somatostatin; D011333:Pro-Opiomelanocortin; D003907:Dexamethasone; D000324:Adrenocorticotropic Hormone; D004247:DNA; D000242:Cyclic AMP; D015500:Chloramphenicol O-Acetyltransferase; D017868:Cyclic AMP-Dependent Protein Kinases