P53 Biomaker and Intervention in Occupational Cancer

描述：职业性癌症的研究方法有待发展 工作场所暴露对健康不利影响的早期标志，并设计 中断工作场所暴露和结果之间的途径的方法 癌症。P53抑癌基因产物是两者的潜在靶点 这些方法中的一种。某些职业暴露会导致基因突变 引起与循环中的p53产生免疫反应的P53 自身抗体，甚至在临床可检测到的癌症发生之前， 因此，这些抗体可以作为不良反应的有用早期标志物。 此外，来自P53的某些短肽序列已在 细胞培养能够使突变的p53恢复正常功能， 导致含有突变型p53的癌细胞死亡，但没有效果 在带有野生型p53的正常细胞上，这表明这可能是一种有用的 一种阻断工作场所暴露之间的途径的方法 P53突变和由此产生的癌症。拟议研究的目的是 检查石棉引起的职业性癌症的这两种方法 在两个相关项目中暴露。在第一个项目中，储存了血清样本 将对患有石棉肺的工人进行检查以确定是否存在 酶联免疫吸附试验和免疫印迹法检测P53自身抗体 以确定抗体的存在是否与随后的 癌症的发展，以及与P53突变的存在有关 由此产生的肿瘤。对于第二个项目，p53在细胞培养中的作用 多肽序列(以多肽或以质粒为基础的微基因形式传递) 石棉相关肺癌和间皮瘤细胞系 P53突变和相应的野生型p53非癌细胞株将 被研究，以及确定多肽的作用机制 在这些细胞中诱导死亡。

DESCRIPTION: Research Methods for Occupational Cancer are needed to develop early markers of adverse health effects from workplace exposures and to devise ways for interrupting the pathways between workplace exposures and resultant cancers. The p53 tumor suppressor gene product is a potential target for both of these approaches. Certain occupational exposures can produce mutations in p53 which cause the generation of an immune response with circulating p53 auto-antibodies, even before the occurrence of clinically detectable cancers, so that these antibodies may serve as useful early markers of adverse effects. In addition, certain short peptide sequences from p53 have been demonstrated in cell culture to be able to cause mutant p53 to revert to normal function, resulting in the death of cancer cells containing mutant p53 but with no effect on normal cells with wild-type p53, suggesting that this may be a useful approach for interrupting the pathway between workplace exposures that produce p53 mutations and resultant cancers. The purpose of the proposed research is to examine both of these approaches for occupational cancers caused by asbestos exposure in two related projects. For the first project, banked serum samples from a cohort of workers with asbestosis will be examined for the presence of p53 auto-antibodies by enzyme-linked immunosorbent assay and ininiunoblotting to determine if the presence of the antibodies correlates with the subsequent development of cancer, as well as with the presence of p53 mutations in the resultant tumors. For the second project, the effects in cell culture of a p53 peptide sequence (delivered as the peptide or as a plasmid-based mini-gene) on asbestos-associated lung cancer and mesothelioma cell lines with and without p53 mutations and corresponding non-cancer cell lines with wild-type p53 will be investigated, as well as determining the mechanism of action of the peptide for inducing death in these cells.