Salicylate-induced growth arrest is associated with inhibition of p70<SUP>s6k</SUP> and down-regulation of c-Myc, cyclin D1, cyclin A, and proliferating cell nuclear antigen

作     者：Law, BK Waltner-Law, ME Entingh, AJ Chytil, A Aakre, ME Norgaard, P Moses, HL 

作者机构：Vanderbilt Univ Vanderbilt Ingram Canc Ctr Nashville TN 37232 USA Vanderbilt Univ Dept Cell Biol Nashville TN 37232 USA Vanderbilt Univ Dept Mol Physiol & Biophys Nashville TN 37232 USA Glostrup Univ Hosp Inst Pathol Anat DK-2600 Glostrup Denmark 

出 版 物：《JOURNAL OF BIOLOGICAL CHEMISTRY》 (生物化学杂志)

年 卷 期：2000年第275卷第49期

页      面：38261-38267页

核心收录：

学科分类：0710[理学-生物学] 071010[理学-生物化学与分子生物学] 07[理学] 

基　　金：NCI NIH HHS [CA42572  CA85492] Funding Source: Medline 

主　　题：醋氨酚/药理学 镇痛药/药理学 消炎药 非甾类/药理学 阿司匹林/药理学 细胞分裂/药物作用 细胞分裂/生理学 细胞系 细胞周期蛋白A/遗传学 细胞周期蛋白D1/遗传学 表皮生长因子/药理学 基因表达调控/药物作用 基因 myc 吲哚美辛/药理学 胰岛素样生长因子Ⅰ/药理学 丝裂原激活蛋白激酶类/代谢 增殖细胞核抗原/遗传学 原癌基因蛋白质c-myc/遗传学 核糖体蛋白质S6激酶类/拮抗剂和抑制剂 水杨酸盐类/药理学 十四酰佛波乙酯/药理学 p38丝裂原活化蛋白激酶类 动物 人类 小鼠 

摘      要：Salicylate and its pro-drug form aspirin are widely used medicinally for their analgesic and anti-inflammatory properties, and more recently for their ability to protect against colon cancer and cardiovascular disease, Despite the wide use of salicylate, the mechanisms underlying its biological activities are largely unknown. Recent reports suggest that salicylate may produce some of its effects by modulating the activities of protein kinases. Since we have previously shown that the farnesyltransferase inhibitor L-744,832 inhibits cell proliferation and p70(s6k) activity, and salicylate inhibits cell proliferation, we examined whether salicylate affects p70(s6k) activity. We find that salicylate potently inhibits p70(s6k) activation and phosphorylation in a p38 MAPK-independent manner. Interestingly, low salicylate concentrations (less than or equal to 250 muM) inhibit p70(s6k) activation by phorbol myristate acetate, while higher salicylate concentrations (greater than or equal to5 mM) are required to block p70(s6k) activation by epidermal growth factor + insulin-like growth factor-1, These data suggest that salicylate may selectively inhibit p70(s6k) activation in response to specific stimuli. Inhibition of p70(s6k) by salicylate occurs within 5 min, is independent of the phosphatidylinositol 3-kinase pathway, and is associated with dephosphorylation of p70(s6k) on its major rapamycin-sensitive site, Thr(389). A rapamycin-resistant mutant of p70(s6k) is resistant to salicylate-induced Thr(389) dephosphorylation.