C-ABL ONCOGENE IN RADIATION INDUCED THYROID CARCINOMA

辐射诱发甲状腺癌中的 C-ABL 癌基因

• 批准号: 3189967
• 负责人: SAYEEDA B ZAIN
• 金额: $ 13.97万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-02-01 至 1992-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3189967
• 关键词: Abelson leukemia virus; antibody formation; antibody specificity; chronic leukemia; chronic myelogenous leukemia; complementary DNA; disease /disorder model; gene expression; genetic library; genetic manipulation; genetic mapping; genetic transcription; genetic translation; ionizing radiation; laboratory rat; messenger RNA; neoplasm /cancer genetics; neoplastic cell culture for noncancer research; nucleic acid probes; oncogenes; phosphorylation; protein biosynthesis; protein tyrosine kinase; radiation carcinogenesis; thyroid neoplasm; transfection

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.

越来越多的证据表明，细胞癌基因（c-oncs）可能是 许多肿瘤过程的重要参与者。 小 然而，人们的注意力已转向c-oncs的作用， 在辐射致癌作用中。 这份提案详细说明了一项研究计划， 癌基因在辐射致癌中的作用 体内大鼠甲状腺模型系统。 该提案具体涉及 与c-abelson癌基因（c-abl）及其转录调控的关系 和易位产物。 95%的CML患者 （慢性粒细胞白血病）嗜中性粒细胞染色体是 目前，这是22号染色体断裂的结果， 指定为巴塞尔公约区域的具体地点，以及 携带V-ABL类似序列的9号染色体。 初步研究表明，c-abl特异性mRNA来源于 从这些辐射诱导的大鼠肿瘤中定性地分离， 从正常人中表达的c-abl特异性mRNA定量 大鼠甲状腺细胞 这是已知的第一个c-abl的例子 癌基因参与非造血来源的肿瘤。 我们计划详细研究c-abl癌基因以及它的 转录和翻译产物。 肿瘤的差异 和非肿瘤c-abl特异性DNA将通过 限制性内切酶，Southern印迹分析，EM异源双链 c-abl特异性序列的分析和核酸测序 分离自基因组和cDNA文库。 控制元件 将表征来自肿瘤组织的c-abl癌基因的特征， 与正常基因相比。 将进行北方印迹分析。 以进一步表征正常和肿瘤组织的mRNA。 Western印迹分析将用于比较肿瘤和非肿瘤 proteins. 肿瘤中c-abl特异性蛋白的研究将进一步 通过肽图谱和酪氨酸测定研究 激酶活性。 其中一种肿瘤（IR 6） 在NIH的DNA介导的基因转移试验中反应良好- 3 T3细胞，并证实ras/k癌基因的参与。 将检查使用该测定法的c-abl序列的状态 这些研究又包括了另外七种这样的肿瘤。 这些调查应提供洞察的作用c-abl 在这种辐射致癌模型中， 了解c-abl癌基因的正常功能。