C-ABL ONCOGENE IN RADIATION INDUCED THYROID CARCINOMA

越来越多的证据表明细胞癌基因（c-oncs）可能是

Growing evidence indicates cellular oncogenes (c-oncs) may be important participants in many neoplastic processes. Little attention, however, has been directed towards the role of c-oncs in radiation carcinogenesis. This proposal details a plan to study the role of oncogenes in radiation induced carcinogenesis using an in vivo rat thyroid model system. The proposal specifically deals with the role of c-abelson oncogene, (c-abl) and its transcriptional and translocational products. In 95% of the patients with CML (chronic myelogenous leukemia) philadelphia chromsome is present, which is the result of breakage of chromosome 22 at a specific site designated bcr, and integration of a segment of chromosome 9 harboring the v-abl analogous sequences. Preliminary studies revealed the c-abl specific mRNA derived from these radiation induced rat tumors differes qualitatively and quantitatively from the c-abl specific mRNAs expressed in normal rat thyroid cells. This is the first known example of c-abl oncogene involvement in a tumor of nonhaematopoietic origin. We plan to study in detail the c-abl oncogene as well as its transcriptional and translational products. Differences in tumor and nontumor c-abl specific DNA will be determined by restriction enzymology, Southern blot analysis, EM heteroduplex analysis and nucleic acid sequencing of c-abl specific sequences isolated from genomic and cDNA libraries. The control elements of the c-abl oncogene from tumor tissue will be characterized and compared with the normal gene. Northern blot analysis will be done to further characterize the mRNA normal and tumor tissues. Western blot analysis will be used to compare tumor and nontumor proteins. c-abl specific protein from the tumors will be further studied by peptide mapping and determination of the tyrosine kinase activity on immunoprecipitates. One of these tumors (IR6) responds well in the DNA mediated gene transfer assays in NIH- 3T3 cells and we have proven the involvment of ras/k oncogene. The status of c-abl sequences using this assay will be examined and these studies elaborated to include seven more such tumors. These investigations should provide insight into the role of c-abl in this model of radiation carcinogenesis and may lead to a better understasnding of the normal function of the c-abl oncogene.