CELL SENESCENCE, CARCINOGENESIS, AND AGING

癌症仍然是与老龄化相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，这可能提供对 癌症和衰老过程。我们已经证明， 癌细胞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 衰老基因到近10条染色体上。细胞衰老是一种 不可逆的细胞周期停滞状态，即正常细胞不能进入 在血清刺激下转化为DNA合成。我们检查了是否 G1/S细胞周期所需蛋白质不可逆转 在衰老的人成纤维细胞中表达下调。与年轻形成对比 两种形式的MAP-K在酪氨酸上被磷酸化的细胞 对血清的反应，p42MAP-激酶不是酪氨酸。 在血清刺激下被磷酸化，而p44MAP-K是 血清中酪氨酸的磷酸化-饥饿或血清刺激 衰老的细胞。Cdc2和细胞周期蛋白A的mRNAs完全失活- 在衰老的成纤维细胞中受到调节。重组表达载体的构建及表达 人类周期蛋白A或cdc2基因在相似人群中衰老 到控制程序。在细胞中观察到寿命显著延长 表达了转染人细胞周期蛋白A和cdc2基因， 提示这两种蛋白质可能在控制病毒感染过程中起重要作用。 细胞的寿命。我们研究了磷酸酶在体内的可能作用。 衰老。金黄地鼠和人成纤维细胞静息状态的实验研究 允许使用磷酸酶抑制剂(原钒酸钠或冈田酸) 细胞从GO/G1期进入S期。在磷酸酶中 抑制剂处理的静止的叙利亚仓鼠胚胎成纤维细胞， Rb和MAP蛋白的磷酸化与cdc2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效果。磷酸酶抑制剂可能 也可以阻止衰老细胞中的DNA合成。这 提示蛋白磷酸酶可能在阴性反应中起作用。 调节细胞生长，维持生长停滞。

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.