title: Modulation of the beta-adrenergic receptor-coupled adenylate cyclase by chemical inducers of differentiation: effects on beta receptors and the inhibitory regulatory protein Gi.
abstract: Several drugs known to induce differentiation in tumor cells were analyzed for their effects on the beta-adrenergic receptor-coupled adenylate cyclase system in two human carcinoma cell lines, HeLa and A431. Each of the drugs was tested alone or in combination with sodium butyrate (NaBu), a known inducer of this signal transduction system. Puromycine amino nucleoside (PMAN) caused the largest increase in beta-adrenergic receptors in HeLa cells followed by hexamethylenebisacetamide (HMBA) whereas 5'-azacytidine (5AZC) was ineffective. In addition, PMAN but not the others acted together with NaBu to elevate receptor levels 12-fold over control values. In contrast, HMBA and 5AZC were much more effective on A431 cells, PMAN caused only a slight increase in beta receptors and none of the drugs acted in concert with NaBu. The increase in beta receptors was usually accompanied by a corresponding increase in isoproterenol-stimulated adenylate cyclase activity. These effects of the drugs appeared to require protein synthesis as they were blocked by cycloheximide. In addition, some of the drugs caused a substantial decrease in basal adenylate cyclase activity. This effect on basal activity was abolished in cells treated with pertussis toxin, which ADP-ribosylates the inhibitory GTP-binding protein, Gi. Both HeLa and A431 cells contained a 41 kDalton substrate for the toxin which corresponds to the alpha subunit of Gi. The Gi subunit was ADP-ribosylated by the toxin to a similar extent in membranes from control and drug-treated cells. Thus, the drugs appear to induce quantitative changes in beta-adrenergic receptors and qualitative changes in Gi which results in a highly responsive beta-adrenergic-stimulated adenylate cyclase.
authors: Developmental and Metabolic Neurology Branch, National Institute of Neurological and Communicative Disorders and Stroke, Bethesda, Maryland 20892.
authors: S
authors: S
authors: Kassis
authors: M
authors: M
authors: Sullivan
authors: P H
authors: PH
authors: Fishman
mesh_terms: D000081:Acetamides / Q000494:pharmacology*; D000262:Adenylyl Cyclases / Q000378:metabolism*; D001374:Azacitidine / Q000494:pharmacology; D002087:Butyrates / Q000494:pharmacology; D020148:Butyric Acid; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D004790:Enzyme Induction / Q000187:drug effects; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006367:HeLa Cells / Q000201:enzymology; D006801:Humans; D009374:Neoplasms, Experimental / Q000201:enzymology; D011691:Puromycin / Q000031:analogs & derivatives*; D011692:Puromycin Aminonucleoside / Q000494:pharmacology*; D011943:Receptors, Adrenergic, beta / Q000187:drug effects*
chemical_list: D000081:Acetamides; D002087:Butyrates; D011943:Receptors, Adrenergic, beta; D020148:Butyric Acid; D011691:Puromycin; D011692:Puromycin Aminonucleoside; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; C014026:hexamethylene bisacetamide; D001374:Azacitidine