CELL SENESCENCE, CARCINOGENESIS, AND AGING

细胞衰老、癌变和衰老

• 批准号: 2574318
• 负责人: J C BARRETT
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 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/2574318
• 关键词: carcinogenesis; cell cycle; cell senescence; enzyme activity; fibroblasts; guanine nucleotide binding protein; hamsters; human tissue; neoplasm /cancer genetics; neoplastic growth; oncoproteins; phosphoprotein phosphatase; polymerase chain reaction; species difference; telomerase; telomere; 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 chromosome 1. We are cloning this putative senescence gene by several approaches including radiation reduction hybrids, genetic suppressor element technology, and PCR differential display. Senescent cells are irreversibly arrested and fail to enter into DNA synthesis upon serum stimulation. Current efforts are involved in investigating the mechanism responsible for the arrest. We have shown that the permanent hypophosphorylation of the Rb protein maybe caused by the inhibition of Rb-kinases (such as cdk4 and cdk6) by elevation of p21 and p16. The hypophosphorylation of Rb allows the formation of Rb-E2F complexes. In addition, two new E2F complexes containing the p21 protein are also found in senescent cells. These complexes most likely negatively regulate genes that are required for entry into DNA synthesis, and hence play an important role in the maintenance of the senescent phenotype. We are continuing to investigate the function of these complexes in several cellular systems, and how loss of their expression may influence the cancer process. Finally, work from other labs suggests that reactivation of telomerase occurs with a high frequency in cells undergoing immortalization. We have found, however,that telomerase activity is low in senescent human fibroblasts but is maintained in senescent hamster fibroblasts. This difference is interesting, because it may account for the difference between species and their immortalization rate, or may indicate that downregulation of teomlerase is not an absolute requirement for senescence. We are investigating these species differences to resolve these issues.

导致癌症的因素是老年人的主要健康问题 是未知的。 我们正在通过研究老龄化来解决这个问题， 在分子水平上使用细胞模型。 我们已经表明， 肿瘤细胞中的衰老程序通过引入 特定的正常人类染色体，包括1号染色体。 我们 通过几种方法克隆了这个假定的衰老基因，包括 减少辐射的杂交种，基因抑制元件技术， PCR差异显示。衰老细胞被不可逆地阻止， 在血清刺激下不能进入DNA合成。 目前的努力 参与调查负责逮捕的机制。 我们已经证明Rb蛋白的永久性低磷酸化 可能是由于Rb激酶（如cdk4和cdk6）被抑制所致， p21和p16升高。Rb的低磷酸化使得 Rb-E2F复合物的形成。 此外，两个新的E2F复合物 在衰老细胞中也发现了含有p21蛋白的细胞。 这些 复合物最有可能负调控基因， 进入DNA合成，并因此发挥重要作用， 衰老表型的维持。 我们正在继续调查 这些复合物在几个细胞系统中的功能，以及如何损失 它们的表达可能会影响癌症的进程。 最后，工作从 其他实验室表明，端粒酶的重新激活发生在高水平的 在经历永生化的细胞中的频率。 我们发现， 然而，在衰老人成纤维细胞中端粒酶活性较低 但维持在衰老的仓鼠成纤维细胞中。 这种差异是 有趣的是，它可以解释物种之间的差异， 以及它们的永生化率，或者可能表明， teomlerase不是衰老的绝对必需品。我们 研究这些物种差异来解决这些问题。