Egr-1 Activates Basic Fibroblast Growth Factor Transcription MECHANISTIC IMPLICATIONS FOR ASTROCYTE PROLIFERATION

摘要: The mechanisms controlling the proliferation of astrocytes are great interest but not well defined. We have previously shown that endogenous neuropeptides, endothelin-3 (ET-3), and atrial natriuretic peptide (ANP), modulate through positively negatively regulating transcription immediate-early gene egr-1 which transactivates basic fibroblast growth factor (bFGF) by unknown mechanisms. In these studies, we determined involvement MAP kinase (Erk) activation ET-3 in egr-1, molecular determinants Egr-1 bFGF. Transfection with a mitogen-activated protein (MAP) (MAPK) expression vector increased cotransfected egr-chloramphenicol acetyltransferase (CAT) construct 3-fold. This induction was totally abolished dominant negative MAPK mutant. A 3-fold egr-CAT significantly reduced treatment ANP, or plasmid. Using mobility shift assays, showed induced bound specifically to several early growth-related (Egr-1) binding sites on bFGF promoter, this effect reversed ANP. also found Sp1 transcriptional at same sites, stimulated ET-3. Deletion experiments indicated only site −160 bp promoter significant for transactivation Egr-1. conclude astrocyte mitogen, ET-3, stimulates related mechanism, specific noncanonical, promoter. ANP inhibits each steps, providing pathway its anti-proliferative action.