Interferon-alpha inhibits chromogranin A promoter activity in neuroendocrine pancreatic cancer cells.
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.
Plath
T
T
Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Universitätsklinikum Charité, Campus Virchow-Klinikum, Humboldt Universität, Berlin, Germany.
Höcker
M
M
Riecken
E O
EO
Wang
T C
TC
Wiedenmann
B
B
Rosewicz
S
S
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
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