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The Role of the P53 Tumour Suppressor Gene as a Determinant of Intrinsic Cellular Radiosensitivity

出版	University of Toronto, 1997
URL	http://books.google.com.hk/books?id=eP5PzwEACAAJ&hl=&source=gbs_api

註釋The intrinsic radiosensitivity of tumour cells is an important factor in tumour radiocurability, but the genetic basis underlying the relative radiosensitivity of mammalian cells remains largely unknown. The wild type p53 (WTp53) protein can mediate a G1 cell cycle arrest or apoptosis following exposure to ionizing radiation depending on cell type. Since many tumours contain mutations in the p53 gene, it is important to examine whether tumour cell radiosensitivity and/or clinical tumour radiocurability can be modified by alterations in the cellular function of WTp53 proteins. The work presented in this thesis describes the relationship between the intrinsic radiosensitivity of transformed rodent cells and the cellular function of wild type p53 protein. Initial results had indicated that rat embryo fibroblasts (REF cells) transfected with an exogenous highly-transforming missense-mutant p53 allele (MTp53-pro193) were relatively radioresistant when compared to untransfected controls and had suggested that radioresistance was correlated to the relative expression of the exogenous MTp53 allele. These initial studies were further supported by similar results in E7/ras-transformed REF transformants expressing an endogenous mutant p53 gene. In the studies presented here, REF transformant clones were transfected with a variety of MTp53 alleles and radioresistance was shown to be associated with an abrogated G1 cell cycle checkpoint response, an increased proficiency at rejoining DNA double-strand breaks (dsb) under continuous low-dose rate irradiation, and the relative expression of the exogenous MTp53 protein. In further studies, murine embryo (MEF) transformants which expressed a MTp53 allele in the absence of endogenous WTp53 protein expression were also found to acquire relative clonogenic radioresistance suggesting a novel "gain of function" property of selected MTp53 proteins in mediating this phenotype. The radioresistance associated with transfection of MTp53 was also shown to be independent of tumourigenicity and spontaneous metastatic potential among the series of REF transformants. This observation suggests that novel clinical strategies designed to overcome oncogene-mediated radioresistance could potentially impact on overall survival, as gains in local tumour control would not be circumvented by an increased probability of distant metastases.