title: Interferon-alpha inhibits chromogranin A promoter activity in neuroendocrine pancreatic cancer cells.
abstract: Interferon-alpha (IFN-alpha) treatment can suppress the hypersecretion syndrome associated with functional neuroendocrine tumors. Chromogranin A (CgA) is a matrix protein of neuroendocrine secretory vesicles and appears to be essential for an appropriate neuroendocrine secretory function. To test the hypothesis that IFN-alpha can directly interfere with CgA gene transcription, we performed transient transfection studies in pancreatic neuroendocrine tumor cells employing CgA-luciferase reporter gene constructs showing that IFN-alpha inhibited basal and protein kinase C-dependent CgA promoter activity. Using 5'-deletion constructs in combination with mutational analysis of the proximal CgA core promoter, a cyclic AMP response element (CRE) at -71 to -64 bp was identified as the IFN-alpha response element of the CgA gene. Furthermore, functional studies indicated that IFN-alpha exerts its effect on the CgA promoter via interference with CRE binding protein (CREB)/CREB binding protein (CBP)-dependent transactivation of the CgA-CRE.
authors.affiliation: Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Universitätsklinikum Charité, Campus Virchow-Klinikum, Humboldt Universität, Berlin, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Plath
authors.forename: M
authors.initials: M
authors.lastname: Höcker
authors.forename: E O
authors.initials: EO
authors.lastname: Riecken
authors.forename: T C
authors.initials: TC
authors.lastname: Wang
authors.forename: B
authors.initials: B
authors.lastname: Wiedenmann
authors.forename: S
authors.initials: S
authors.lastname: Rosewicz
mesh_terms: D000818:Animals; D050882:CREB-Binding Protein; D053379:Chromogranin A; D002864:Chromogranins / Q000235:genetics* / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D008156:Luciferases / Q000235:genetics; D051379:Mice; D018358:Neuroendocrine Tumors; D009687:Nuclear Proteins / Q000235:genetics; D010190:Pancreatic Neoplasms; D011401:Promoter Regions, Genetic; D011493:Protein Kinase C / Q000378:metabolism; D017384:Sequence Deletion; D015534:Trans-Activators / Q000235:genetics; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: C506150:CHGA protein, human; D053379:Chromogranin A; D002864:Chromogranins; D017362:Cyclic AMP Response Element-Binding Protein; D016898:Interferon-alpha; D009687:Nuclear Proteins; D015534:Trans-Activators; C506155:chromogranin A, mouse; D008156:Luciferases; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; C494364:Crebbp protein, mouse; D011493:Protein Kinase C