Alternations of the Transcriptional Co-activator p300 in Oral Cancers and Its Novel Role in Tumor Suppression

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The p300 acetyltransferase and transcriptional coactivator plays key roles in the regulation of cell proliferation and differentiation. p300 is targeted by viral oncoproteins, and mutations of p300, accompanied by inactivation of the second allele, have been reported in certain types of cancers, carcinomas. Nevertheless, a role for p300/CBP in human tumorigenesis is still remains poorly understood.In this study, We have identified p300 mutations associated with the inactivation of the second allele in two lines of human carcinoma cells. First, we identified a homozygous p300 deletion of exons 15-18 in the SiHa cervical carcinoma cell line, which results in an in-frame deletion that causes specific loss of the bromodomaimt, a conserved domain implicated in the regulation of HAT activity (Ohshima et al. 2001). In addition, we found two point mutations in the human oral squamouse cell carcinoma HOC313 ; a missence mutation within the E1A binding region, and a nonsense mutation leading to … More a loss of the C-terminal Q-rich and SRC/p160 binding domains (Suganuma et al. submitted).Next, we investigated the ability of p30O to suppress the growth of cells lacking normal counterparts and the effects of p300 mutations on cell growth control and transcriptional regulation. We demonstrate that reintroduction of wild-type p300 suppressed growth of human carcinoma cells lacking normal p300 and the tumor-derived mutants lost suppressive activity. Furthermore, responses to TGFβ signaling, which is important for the negative regulation of epithelial cell growth, were severely impaired in the p300-deficient cells and wild-type expression restored responsiveness (Suganuma et al. submitted). We also show that multiple, distinct functions of p300 important for its chromatin remodeling and coactivator activities play critical roles in both the suppression of tumor cell growth and transcriptional regulation involved in negative regulation of cell growth. These results provide the first experimental evidence that p30O acts as a suppressor of carcinoma cell growth, and shed light on a role for p30O in epithelial malignancies. Less