Involvement of co-activator p300 in the transcriptional regulation of the HER-2/neu gene.

Overexpression of HER-2/neu is frequently found in human cancer and has been shown to enhance the metastatic potential of tumors and to induce the chemoresistance of cancer cells. The molecular mechanism(s) by which HER-2/neu expression is deregulated in cancer is not clear. We reported previously that adenovirus 5 E1A is capable of transcriptionally repressing the HER-2/neu promoter. We report here that the E1A-associated p300 protein can derepress the E1A-mediated repression of HER-2/neu in a dose-dependent manner. A p300 mutant, which lost its ability to bind to E1A, also effectively rescued the repressed HER-2/neu promoter in the presence of excess E1A inside the cells. A protein complex can bind to the p300 consensus sequences in HER-2/neu promoter. The intensity of the retarded band of the protein complex decreased significantly after preincubation of the nuclear extracts with beads that has been conjugated with anti-p300 antibody. The binding of E1A to p300 and the p300 consensus sequence in HER-2/neu promoter were crucial for the ability of E1A to repress HER-2/neu promoter, demonstrating that p300 is involved in the transcriptional regulation of HER-2/neu and serves as a target for E1A repression.