Carcinogenic Interactions of Radiation and Chemicals

我们先前证明了敏感BALB/cByJ和抗性C57 BL/6 ByJ小鼠之间对辐射诱导的乳腺癌和辐射诱导的细胞遗传学不稳定性的易感性的品系差异，并提供了这种易感性差异是可遗传性状的证据。从这些菌株的cDNA序列分析表明两个独特的BALB/c小鼠的多态性。对两个品系、F1杂交种和回交动物的研究表明，对辐射诱导的细胞遗传学不稳定性的敏感性与编码DNA依赖性蛋白激酶催化亚基的基因Prkdc之间存在显著关联。BALB/c Prkdc等位基因纯合子小鼠（Prkdc BALs ′ c）也缺乏双链断裂的辐射后修复，显示激酶活性降低，Western分析显示DNA-PKcs信号强度降低。由于修复缺陷，减少西方信号强度，降低激酶活性，以及这两个多态性的存在都显着与辐射诱导的细胞遗传学不稳定性的易感性增加，我们现在建议检查该基因座和辐射诱导的乳腺癌易感性之间的遗传连锁，并更直接地illucidate的作用Prkdc BALB/cin辐射诱导的不稳定性和乳腺癌。我们现在还证明，照射来自BALB/c以及SCID的乳腺细胞，其具有Prkdc的截短突变，导致端粒和辐射诱导的双链断裂（DSB）之间的融合，推测这是由于作为端粒维持中的重要元素的DNA-PKcs的功能缺陷。具体而言，该项目的目的是：1）直接确定PrkdcBALB中多态性的功能后果; 2）确定Prkdc BALB在辐射诱导的乳腺癌易感性中的作用; 3）确定端粒功能障碍在辐射诱导的细胞遗传学不稳定性和乳腺癌中的作用。性能现场=

EXCEED THE SPACE We previously demonstrated strain differences in susceptibility to radiation-induced mammary cancer and radiation- induced cytogenetic instability between sensitive BALB/cByJ, and resistant C57BL/6ByJ mice and provided evidence that such susceptibility differences were heritable traits. Sequence analysis of cDNA from these strains indicate two polymorphisms unique to the BALB/c mouse. Studies in the two strains, F1 hybrids, and in backcross animals have demonstrated a significant association between susceptibility to radiation-induced cytogenetic instability and Prkdc, the gene encoding the catalytic subunit of DNA dependent protein kinase (DNA PKcs). Mice homozygous for the BALB/c Prkdc allele (Prkdc BALs'c) are also deficient in the post-irradiation repair of double strand breaks, showed a reduced kinase activity, and western analyses showed a reduced intensity of signal for DNA-PKcs. Since the repair deficiency, reduced western signal intensity, reduced kinase activity, and the presence of these two polymorphisms are all significantly associated with increased susceptibility to radiation-induced cytogenetic instability, we now propose to examine the genetic linkage between this locus and susceptibility to radiation-induced mammary cancer, and to more directly illucidate the role of Prkdc BALB/cin radiation-induced instability and mammary cancer. We have now also demonstrated that irradiation of mammary cells from BALB/c as well as SCID, which have a truncating mutation of Prkdc, results in fusions between telomeres and radiation-induced double strand breaks (DSB) presumably as a result of a defect in the function of DNA- PKcs as an important element in telomere maintenance. Specifically, the aims of this project are to: 1) directly determine the functional consequence of polymorphorisms in PrkdcBALB; 2) determine the role of Prkdc BALB in susceptibility to radiation-induced mammary cancer; 3) determine the contribution of telomere dysfunction in radiation-induced cytogenetic instability and mammary cancer. PERFORMANCE SITE ========================================Section End===========================================