P53 Regulation of Uridine Phosphorylase Activity, Pyrimidine Salvage Pathway and Their Effects on Breast Cancer Therapy

摘要

This research project has been focused on the elucidation of the mechanisms affecting the therapeutic efficacy of fluoropyrimidines to improve the clinical outcome of breast cancer patients. Based on the findings of the last scientific year that the nullification in ES cells of uridine phosphorylase (UPase) leads to a significantly increased cell resistance to fluoropyrimidines and that wild-type p53 protein down-regulates UPase expression, we have focused our research on the following two areas: 1) Elucidation of the p53 regulation mechanism(s) of UPase expression; In this investigation, we demonstrated that wild-type p53 protein represses UPase gene expression via sequence-specific DNA binding at promoter level, and that the mutations of p53 leads to loss of this regulatory function. 2) In vivo study of UPase function in fluoropyrimidine metabolism and uridine regulation. In order to better translate the basic research understanding to the clinical service, we have extended our first year's findings on UPase knockout ES cell to in vivo study through generation and use of UPase knockout mouse model. The research results defined the important role in vivo of UPase in fluoropyrimidine metabolism and uridine regulation in plasma and tissue.