Huang N N, Wang D J, Heppel L A
Section of Biochemistry, Molecular and Cell Biology, Cornell University, Ithaca, New York 14853.
J Biol Chem. 1993 May 25;268(15):10789-95.
The mitogenic effect of extracellular ATP on IMR-90 human fibroblasts subjected to in vitro aging was studied. ATP stimulated DNA synthesis and cell proliferation in young cells as much as epidermal growth factor (EGF) or insulin, while it stimulated aged cells to a much greater extent than seen for any other growth factor tested. When combined with EGF or insulin, ATP restored the greatly reduced mitogenic responsiveness of aged cells nearly to the level noted for young cells. Addition of prostaglandin E2 or other agents that elevate cAMP levels resulted in inhibition of DNA synthesis stimulated by EGF or insulin. Furthermore, the basal release of arachidonic acid and prostaglandin E2 and the endogenous levels of cAMP rose during aging and became much greater than in young cells. All three of these changes were suppressed by extracellular ATP. ATP-dependent suppression of cAMP accumulation was pertussis toxin-sensitive. Protein kinase C down-regulation inhibited arachidonate metabolism and enhanced DNA synthesis stimulated by ATP. These studies suggest that ATP exerts its mitogenic effect, especially on aged IMR-90 cells, at least partially by suppression of arachidonate metabolism.
研究了细胞外ATP对体外老化的IMR - 90人成纤维细胞的促有丝分裂作用。ATP刺激年轻细胞中的DNA合成和细胞增殖的程度与表皮生长因子（EGF）或胰岛素相同，而它对老化细胞的刺激程度比所测试的任何其他生长因子都要大得多。当与EGF或胰岛素联合使用时，ATP几乎将老化细胞大大降低的有丝分裂反应性恢复到年轻细胞的水平。添加前列腺素E2或其他提高cAMP水平的试剂会导致EGF或胰岛素刺激的DNA合成受到抑制。此外，花生四烯酸和前列腺素E2的基础释放以及cAMP的内源性水平在老化过程中升高，且比年轻细胞中的水平高得多。所有这三种变化都被细胞外ATP抑制。ATP依赖性cAMP积累的抑制对百日咳毒素敏感。蛋白激酶C下调抑制花生四烯酸代谢并增强ATP刺激的DNA合成。这些研究表明，ATP发挥其促有丝分裂作用，尤其是对老化的IMR - 90细胞，至少部分是通过抑制花生四烯酸代谢实现的。
