Interferon-alpha inhibits chromogranin A promoter activity in neuroendocrine pancreatic cancer cells

Interferon-cr (IFN-a) treatment ran suppress the hypersecretion syndrome as sociated with functional neuroendocrine tumors. Chromogramin A (CpA) is a m atrix protein of neuroendocrine secretory vesicles and appears to be essent ial for an appropriate neuroendocrine secretory function. To test the hypot hesis that IFN-a can directly interfere with CgA gene transcription, we per formed transient transfection studies in pancreatic neuroendocrine tumor ce lls employing CgA-luciferase reporter gene constructs shelving that IFN-a i nhibited basal and protein kinase C-dependent CgA promoter activity. Using 5'-deletion constructs in combination with mutational analysis of the proxi mal CgA core promoter, a cyclic AMP response element (CRE) at -71 to -64 bp was identified as the IFN-cr response element of the CgA gene. Furthermore , functional studies indicated that IFN-cl exerts its effect on the CgA pro moter via interferace,with CRE binding protein (CREB)/CREB binding protein (CBP)-dependent transactivation of the CgA-CRE. (C) 1999 Federation of Euro pean Biochemical Societies.