Cell Senescence, Carcinogenesis, and Aging

细胞衰老、癌变和衰老

• 批准号: 6559271
• 负责人: JAMES C. BARRETT
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6559271
• 关键词: acetylation; aging; cancer risk; carcinogenesis; cell senescence; chromosomes; complementary DNA; disease /disorder model; enzyme activity; enzyme complex; gene expression; genetic promoter element; human genetic material tag; methylation; microarray technology; molecular cloning; neoplastic cell; protooncogene; renal cell carcinoma; subtraction hybridization; telomerase; tissue /cell culture; tumor suppressor genes

The factors that cause cancer to be a major health problem of the elderly are unknown. We are addressing this problem by studying aging at the molecular level using cellular models. We have shown that defects in the senescence program in tumor cells is corrected by introduction of specific normal human chromosomes, including chromosomes 1,2, and 3. We are cloning these putative senescence -genes by combining several approaches including radiation reduction hybrids, TAR cloning, subtractive hybridization, and cDNA microarray analysis. We have shown that a putative senescence gene that functionally acts to suppress the enzyme, telomerase, is localized to chromosome 3. We have shown that the suppression of telomerase activity is due to down-regulation of the expression of the hTERT component of the telomerase enzyme complex. This down-regulation occurs at the level of the RNA. We have cloned the hTERT promoter and have examined elements that interact with E-box elements with the candidate gene on chromosome 3 in addition to conducting extensive analysis of the methylation and acetylation of this promoter. Our work indicates that while c-myc is an important regulator of telomerase in some cells other factors are more likely to be critical in our renal cell carcinoma model.

导致癌症成为老年人主要健康问题的因素尚不清楚。我们正在通过使用细胞模型在分子水平上研究衰老来解决这个问题。我们已经证明，肿瘤细胞衰老程序中的缺陷可以通过引入特定的正常人类染色体（包括1号、2号和3号染色体）来纠正。我们正在结合几种方法克隆这些假定的衰老基因，包括辐射减少杂交，TAR克隆，消减杂交和cDNA微阵列分析。 我们已经表明，一个假定的衰老基因，功能上的作用，以抑制酶，端粒酶，是本地化的3号染色体。我们已经表明，端粒酶活性的抑制是由于端粒酶复合物的hTERT组分的表达下调。这种下调发生在RNA水平。我们已经克隆了hTERT启动子，并检查了与3号染色体上的候选基因的E-box元件相互作用的元件，此外还对该启动子的甲基化和乙酰化进行了广泛的分析。我们的工作表明，虽然c-myc是端粒酶在某些细胞中的重要调节因子，但其他因素在我们的肾细胞癌模型中更可能是关键的。