CELL SENESCENCE, CARCINOGENESIS, AND AGING

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导入特定的正常人类染色体来纠正，包括染色体1、2和3。我们正在结合几种方法来克隆这些可能的衰老基因，包括辐射减少杂交、TAR克隆、消减杂交和基因芯片分析。我们已经证明了一个可能的抑制端粒酶活性的衰老基因定位在3号染色体上。我们已经证明端粒酶活性的抑制是由于端粒酶复合体的hTERT组分的表达下调所致。这种下调发生在RNA水平上。我们已经克隆了hTERT启动子，除了对该启动子的甲基化和乙酰化进行了广泛的分析外，还研究了与E-box元件相互作用的元件和染色体3上的候选基因。我们的工作表明，虽然c-myc是某些细胞中端粒酶的重要调节因子，但在我们的肾细胞癌模型中，其他因素更可能是关键因素。

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.