Studies on molecular mechanism of tumor suppression by the drs gene

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The drs gene was originally isolated as a suppressor gene against v-src transformation. We have shown that expression of drs mRNA was markedly reduced in a variety of human cancer cell lines, and introduction of drs cDNA by retrovirus vector into these cancer cell lines caused suppression of anchorage-independent growth. These findings indicate that downregulation of drs mRNA is closely correlated with expression of malignant phenotype in development of human cancers and the drs gene act as a tumor suppressor. In this project, we performed the research to clarify the mechanism of tumor suppression by the drs gene and obtained the following results.1. Identification of Drs-binding proteinsWe have established the systems to identify Drs-binding proteins by immunoprecipitation and peptide mass fingerprinting methods in cells expressing high level of Drs protein. By using these systems, we found that several cellular proteins including GRF78/BiP and α-glucosidase-α subunit are associated w … More ith Drs.2. Construction and analysis of drs-knockout mouseBy gene-targetting techniques, we succceeded in making germ line-transmitted drs kockout mouse. Analyses of Drs KO mouse on tumor formation and physiological function of the drs gene are in progress.3. Investigation of correlation between expression of malignant phenotypes and downregulation of drs gene in human cancersTo clarify the role of the drs gene in the development of human cancers, we examined the expression of the drs mRNA and the status of genome DMA of drs in normal, benign, and malignant tissues of colon, lung, prostate cancers and lymphomas of ATL We found that drs mRNA was downregulated in malignant tissues of these cancers. Neither gross deletion nor rearrangement of the drs genome was detected in these malignant tissues.4. Apotosis-inducing activity of drs.Wefound that drs can induce apoptosis by activation of caspase-12, -9-, -3 in human cancer cell lines, suggesting a novel apoptosis-mediated pathway of tumor suppression by the drs gene. Less