Regulation and function of tumor suppressor p53 isoforms beta and gamma in Acute Myeloid Leukemia

Abstract

Research has proposed that the C-terminal truncated p53 isoforms beta and gamma enhance chemosensitivity in p53(null) cancer cell lines. Their high expression in acute myeloid leukemia (AML) patients correlates positively with increased survival and response to chemotherapy. However, it is ambiguous whether they have independent functions or act in concert with full-length p53 (FLp53) in AML. Furthermore, resazurin which acts through the generation of reactive oxygen species (ROS) has been demonstrated to have cytotoxic effects in leukemia cells. The generation of ROS has been shown to play roles in p53 regulation but its mechanism is still elusive. In this thesis, the functional roles of p53 beta and p53 gamma in response to chemotherapy and resazurin were investigated in AML cell lines. Also, the effect of resazurin on the regulation of p53 isoforms expression was examined. Results have revealed that p53 beta and p53 gamma may act in concert with FLp53 in a ratio-dependent manner and a high level of p53 gamma is cytotoxic which suggest a prospective therapeutic target of p53 isoforms. Also, it has shown that resazurin causes p53-independent down-regulation of Mdm2 and increased apoptosis which can contribute to the development of a novel therapy in AML.