TELOMERASE IN CELLULAR IMMORTALIZATION

细胞永生化中的端粒酶

• 批准号: 2833737
• 负责人: Martin Lipkin
• 金额: $ 32.23万
• 依托单位: STRANG CANCER PREVENTION CENTER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-06-30 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2833737
• 关键词: cancer prevention; carcinogenesis inhibitor; cell line; cell transformation; chemoprevention; drug screening /evaluation; enzyme inhibitors; neoplasm /cancer genetics; telomerase

Telomeres, the extreme ends of the eukaryotic chromosomes, are tandemly repeated specialized sequences that are implicated in maintaining chromosome stability and providing protection against illegitimate recombination and enzymatic degradation. The shortening of the telomeres is believed to function as a "mitotic clock" eventually signaling senescence when a critical threshold level is reached. Human cells in culture escape senescence and acquire the capability of proliferating indefinitely probably by reactivating or upregulating telomerase and thus stabilizing the chromosomal ends. In contrast to most normal human somatic cells, telomerase activity is detected in immortalized cell lines and in about 85% of human cancers. The upregulation of the telomerase activity is thought to confer upon cancer cells the proliferative capacity to accumulate necessary mutations to become malignant. It is then conceivable that inhibition of the telomerase activity may block immortalization of cells in vitro and acquisition of malignant potential and/or reversal of the malignant phenotype in vivo thus providing "proof of principle" for a causal link between telomerase and cellular immortality and cancer. Telomerase activity is crucial for cellular immortality and carcinogenesis and that telomerase inhibitors, especially against its RNA moiety, may be useful chemopreventive agents. The goal of the study is a) to evaluate telomerase antagonists in validating a causal link between telomerase, cell immortalization, and cancer and b) to assess its appropriateness as a molecular target for chemoprevention.

端粒是真核生物染色体的末端， 串联重复的特化序列， 保持染色体稳定性，并提供保护， 非法重组和酶降解。 缩短 端粒被认为是一个“有丝分裂时钟” 当临界阈值水平达到一定程度时， 达到了培养中的人类细胞逃避衰老， 可能通过重新激活或 上调端粒酶从而稳定染色体末端。 与大多数正常的人体细胞不同， 在永生化细胞系中检测到， 癌的 端粒酶活性的上调被认为是 赋予癌细胞增殖能力， 必要的突变变成恶性肿瘤。 那么可以想象， 端粒酶活性的抑制可能会阻止细胞的永生化。 体外细胞和获得恶性潜能和/或逆转 因此提供了“恶性表型的证据”。 端粒酶和细胞凋亡之间因果关系的“原则” 永生和癌症端粒酶活性对细胞增殖至关重要。 以及端粒酶抑制剂， 特别是针对其RNA部分，可能是有用的化学预防剂， 剂.这项研究的目的是a）评估端粒酶 拮抗剂在验证端粒酶、细胞 永生化和癌症，以及B）评估其作为 化学预防的分子靶点。