Effect of mutation in the p300 transcription coactivator on transcriptional response and cell proliferation of human carcinoma cell lines

Abstract

The p300 and closely related CBP acetyltransferases function as global transcriptional coactivators and play important roles in a broad spectrum of biological processes, including cell proliferation and differentiation. The p300 protein is targeted by viral oncoproteins, and mutations of the p300 gene associated with second allele inactivation have been identified in certain types of human cancers and carcinomas. This study shows that 300 mutants identified in human carcinoma cells retain the capacity to bind p300/CBP interacting proteins, E1A, PCAF, and Smads. However, carcinoma cell lines expressing only mutant p300 severely impaired transcriptional responses to some signaling, including that of TGF beta, which responses have been shown to be mediated by p300 and CBP. Furthermore, tumor-derived p300 mutants did not affect the proliferation of p300-deficient cells in the presence or absence of TGF beta. These results suggest that p300 plays an important role in epithelial carcinogenesis by mediating transcription that negatively regulates cell proliferation.