The glutathione S-transferase family of detoxification enzymes plays a pivotal role in protecting cells from cytotoxic and carcinogenic damage. The contribution of the mu class of isozymes to this function is significant and includes the inactivation of highly reactive epoxides. The potential importance of glutathione S-transferase mu in cancer prevention has been strengthened by the inability of 50% of the population to express this isozyme. Although several studies have suggested that the mu (M1) null genotype may increase one's risk for cancer, this association remains equivocal and requires further investigation. Two independent aspects of glutathione S-transferase mu expression will be addressed in the present study using a recently isolated genomic clone for mouse glutathione S-transferase M1. Based upon our previous identification of the chemopreventive agent oltipraz as a potent inducer of glutathione S-transferase mu expression, we first propose to characterize the 5' regulatory region of the M1 clone and define the nucleotide sequence required for transcriptional activation by oltipraz. The identified element will be sequenced and its importance in the regulation of other detoxification enzymes will be explored. In the second series of experiments, the M1 gene will be disrupted using gene-targeting methodology. Homologous recombination of the targeting vector with chromosomal DNA will ultimately lead to the establishment of a transgenic strain deficient in M1 expression; the only model of the human glutathione S-transferase mu null genotype which is shared by approximately 50% of the population. Transgenic animals will provide a valuable tool with which to examine the coordinate regulation of detoxification enzymes in the absence of M1 and the role of the null genotype in lung and bladder cancer susceptibility. In addition, the contribution of M1 induction to the chemopreventive activity of oltipraz will be examined. Combined analysis of the proposed regulation and transgenic experiments will aid in elucidating the role of M1 in cancer susceptibility and prevention. These findings will provide a basis for the development of new strategies for modulating detoxification enzyme activity and increasing cellular protection in individuals at increased risk for cancer.
| Clapper, M L (2000) Genetic polymorphism and cancer risk. Curr Oncol Rep 2:251-6 |
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