The Roles of Tap63 in P53-Expressing and P53-Deficient Cancer Cells under Genotoxic Stress.

The transcription factor p63 belongs to the p53 protein family and plays an important role in epithelial development. Recent studies showed that p63 is over-expressed in some human squamous cell carcinomas of the head and neck, suggesting a role in carcinogenesis. The p63 gene contains two promoters and alternative promoter usage generates two groups of proteins with (TAp63) or without (ΔNp63) the transactivation domain. Although the roles of TAp63 in epithelial development have been described in numerous recent studies, the regulation of its expression and its roles in cancer have not been elucidated. In our preliminary study, we showed that knockdown of TAp63 expression by shRNA led to increased proliferation of Hep3B cell compared to that of the mock cell, suggesting a growth suppressive effect of TAp63. Moreover, we treated p53-deficient (Hep3B and PC-3) and p53-expressing cells (A549 and HepG2) with doxorubicin to examine the possible roles of TAp63 in these cells under genotoxic stress. TAp63 expression was induced by doxorubicin in p53-deficient cell lines, but not in p53-expressing cell lines. Ectopic expression of p53 in p53-deficient cell (Hep3B) reduced TAp63 promoter activity and knockdown of TAp63 attenuated doxorubicin-induced cell growth arrest by promoting cell cycle progression via increasing the percentage of G2/M cells. Moreover, knockdown of TAp63 increased cell sensitivity to doxorubicin-induced genomic damage. Based on our preliminary results, we suggested that TAp63 plays a compensatory role in p53-deficient cancer cells in cell cycle regulation and DNA damage repair. In this proposal, we intend to further delineate the function of TAp63 in cancer cells under genotoxic stress and the mechanism underlying the TAp63 functions. We will use p53-expressing and p53-deficient cancer cells to study the effect of TAp63 expression on DNA repair, cell cycle regulation and apoptosis. The underlying mechanism of the TAp63 regulated cellular responses will also be studied. Understanding the role and functional mechanism of TAp63 in cancer cells should shed light in cancer research. In this proposal, we present some of our preliminary results and propose our future plan along the line of this research work.

Project ID:PC10007-0351
External Project ID:NSC100-2320-B182-008