CELL SENESCENCE, CARCINOGENESIS, AND AGING

细胞衰老、癌变和衰老

• 批准号: 3755409
• 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/3755409
• 关键词: DNA replication; aging; apoptosis; cancer risk; cell cycle; cell senescence; cellular oncology; cellular pathology; cytogenetics; gene expression; human tissue; neoplasm /cancer classification /staging; neoplastic transformation; phosphatase inhibitor; preneoplastic state; tissue /cell culture; tumor suppressor genes

Cancer remains one of the major health problems associated with aging, yet the role of the aging process in cancer remains to be determined. One approach to this problem is to study aging at the molecular level using cellular models of aging, which may provide insights into both the cancer and the aging processes. We have shown that defects in the senescence program in cancer cells can be corrected by introduction of normal human chromosomes into immortal cells. These studies mapped senescence genes to nearly 10 chromosomes. Cellular senescence is a state of irreversible cell cycle arrest in which normal cells fail to enter into DNA synthesis upon serum stimulation. We examined whether proteins required for G1/S cell cycle progression were irreversibly down-regulated in senescent human fibroblasts. In contrast to young cells where both forms of MAP-kinase were phosphorylated on tyrosine in response to serum, the p42MAP-kinase was not tyrosine phosphorylated upon serum stimulation, whereas p44MAP-kinase was phosphorylated on tyrosine in serum-starved or serum-stimulated senescent cells. Cdc2 and cyclin A mRNAs were completely down- regulated in senescent fibroblasts. Clones expressing the transfected human cyclin A or cdc2 genes senesced at a population doubling similar to controls. Significant extension of life span were seen in cells that expressed both the transfected human cyclin A and cdc2 genes, suggesting that these two proteins may be important in controlling the life span of cells. We investigated the possible role of phosphatases in senescence. Treatment of quiescent hamster and human fibroblasts with phosphatase inhibitors (sodium orthovanadate or okadaic acid) allowed cells to progress from GO/G1 arrest to S-phase. In phosphatase inhibitor-treated quiescent Syrian hamster embryo fibroblasts, phosphorylation of RB and MAP-kinase proteins and induction of cdc2 protein accompanied this progression to DNA synthesis, similar to the effects of serum or mitogen treatment. Phosphatase inhibitors could also override the block to DNA synthesis in senescent cells. This suggests protein phosphatases may play a role in the negative regulation of cell growth and maintenance of growth arrest.

癌症仍然是与衰老有关的主要健康问题之一， 然而，衰老过程在癌症中的作用仍有待确定。 解决这个问题的一种方法是在分子水平上研究衰老 使用衰老的细胞模型，这可能会提供对这两个方面的见解， 癌症和衰老过程。 我们已经表明， 癌细胞中的衰老程序可以通过引入 将正常的人类染色体转化为永生细胞。 这些研究绘制了 近10条染色体的衰老基因。细胞衰老是一种 正常细胞不能进入的不可逆的细胞周期停滞状态 转化为DNA合成 我们研究是否 G1/S细胞周期进程所需的蛋白质是不可逆的 在衰老的人成纤维细胞中下调。 与年轻相比 两种形式的MAP-激酶在酪氨酸上磷酸化的细胞 在对血清的反应中，p42 MAP-激酶不是酪氨酸 磷酸化血清刺激，而p44 MAP-激酶， 在血清饥饿或血清刺激的 衰老细胞 Cdc 2和细胞周期蛋白A mRNA完全下调- 在衰老成纤维细胞中调节。 表达转染的 人类细胞周期蛋白A或cdc 2基因以类似于 控制。 在细胞中观察到寿命的显著延长， 表达转染的人细胞周期蛋白A和cdc 2基因， 这表明这两种蛋白质可能在控制 细胞的寿命。 我们研究了磷酸酶在 衰老 用以下物质处理静止的仓鼠和人成纤维细胞： 允许磷酸酶抑制剂（原钒酸钠或冈田酸） 细胞从G 0/G1期停滞进展到S期。 包含磷酸酶 经导管处理的静止叙利亚仓鼠胚胎成纤维细胞， RB和MAP-激酶蛋白的磷酸化和cdc 2的诱导 蛋白质伴随着DNA合成的进程，类似于 血清或有丝分裂原处理的影响。 磷酸酶抑制剂可以 也能克服衰老细胞中DNA合成的障碍。 这 表明蛋白磷酸酶可能在负作用中起作用。 调节细胞生长和维持生长停滞。