CELL SENESCENCE, CARCINOGENESIS, AND AGING

细胞衰老、致癌和衰老

• 批准号: 3841060
• 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/3841060
• 关键词: DNA replication; aging; carcinogenesis; cell age; cell cycle proteins; cell growth regulation; cell senescence; cellular oncology; embryo /fetus tissue /cell culture; fibroblasts; gene expression; human genetic material tag; human tissue; messenger RNA; neoplastic transformation; phosphatase inhibitor; phosphoprotein phosphatase; phosphorylation; protein biosynthesis; protein tyrosine kinase; tissue /cell culture; transfection

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 human chromosome 1 from normal cells into immortal cells. 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. However, 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 that 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。 一 解决这个问题的方法是在分子水平上研究衰老， 衰老的细胞模型，这可能会提供对癌症和癌症的见解。 以及衰老过程。 我们已经证明衰老过程中的缺陷 在癌细胞中的程序可以通过引入人 从正常细胞转化为永生细胞。 细胞衰老是 一种不可逆的细胞周期停滞状态，其中正常细胞不能 在血清刺激下进入DNA合成。 我们研究是否 G1/S细胞周期进程所需的蛋白质不可逆地下降， 在衰老的人成纤维细胞中调节。 与年轻细胞相反， 这两种形式的MAP-激酶都在酪氨酸上磷酸化， 血清中p42 MAP激酶不被酪氨酸磷酸化 刺激，而p44 MAP-激酶在血清中酪氨酸磷酸化， 饥饿或血清刺激的衰老细胞。 Cdc 2和细胞周期蛋白A mRNA表达水平分别为： 在衰老成纤维细胞中完全下调。 表达 转染的人细胞周期蛋白A或cdc 2基因在群体倍增时衰老 与对照组相似。 然而，寿命显著延长 在表达转染的人细胞周期蛋白A和cdc 2基因的细胞中， 这表明这两种蛋白质可能在控制生命中起重要作用， 细胞的跨度。 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： 磷酸酶抑制剂（原钒酸钠或冈田酸）允许细胞 从Go/G1期阻滞进展到S期 在磷酸酶底物处理的 静止期叙利亚仓鼠胚胎成纤维细胞，RB和MAP的磷酸化， 激酶蛋白和cdc 2蛋白诱导伴随这一进展 对DNA合成的影响，类似于血清或有丝分裂原处理的效果。 磷酸酶抑制剂也可以克服DNA合成的障碍， 衰老细胞 这表明蛋白磷酸酶可能在 在细胞生长的负调节和生长停滞的维持中。