SIGNAL TRANSDUCTION PATHWAYS IN RESPONSE TO STRESS

应对压力的信号传导途径

• 批准号: 6160459
• 负责人: Y LIU
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON AGING
• 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/6160459
• 关键词: aging; arsenic; biological signal transduction; cell proliferation; enzyme activity; epidermal growth factor; liver cells; methane sulfonate; mitogen activated protein kinase; mitogens; peroxides; phosphorylation; protein kinase; stress

Summary of work: This project focusses on the signal transduction pathways mediating stress responses in mammalian cells. Studies over the past year have concentrated on three topics. (1) Identification of upstream regulators of ERK signaling in response to arsenite. We have previously demonstrated that arsenite can differentially activate ERK, JNK and p38 MAP kinases. The activation of ERK is dependent on Ras. Now we have found that arsenite can stimulate the tyrosine phosphorylation of Shc and its interaction with the adaptor protein Grb2. Tyrosine phosphorylation of Shc was concommitant with tyrosine phosphorylation of an unidentified high molecular weight protein, with which it interacts. This protein may function as an activator of Shc during stress, initiating the Ras/ERK signaling cascade. (2) p90RSK activation in response to stress and its relationship with IkB. p90RSK is a serine/threonine protein kinase which lies downstream of ERK, and is therefore activated by mitogenic stimuli. We found that p90RSK can be activated by many stressful conditions including arsenite, H2O2 and methyl methanesulfonate. p90RSK activation was found to correlate with the phosphorylation and degradation of IkB, an inhibitor of the transcription factor NF-kB. p90RSK may function as an IkB kinase and contribute to NF-kB activation during stress. (3) Age-associated decline in p70S6k in EGF-stimulated hepatocytes. Aging is associated with a decline in the proliferative capacity of cells. Previously we showed that this was correlated with decreased ERK activation by mitogenic stimuli. We have now observed that there is also a significant decline in the activity of p70S6k with aging. Thus, defects in at least two distinct signal transduction pathways may account for the age-associated defect in proliferative capacity. Analysis of the upstream regulators common to both pathways may provide important insights into the basic mechanisms of the aging.

工作概述：本项目主要研究信号转导 在哺乳动物细胞中调节应激反应的途径。 来的研究 过去一年集中讨论了三个主题。 (1)ERK信号转导上游调控因子的鉴定 亚砷酸盐。 我们以前已经证明亚砷酸盐可以 差异激活ERK、JNK和p38 MAP激酶。 的激活 ERK依赖于Ras。 现在我们发现亚砷酸盐可以刺激 Shc的酪氨酸磷酸化及其与接头的相互作用 Grb 2蛋白。 Shc的酪氨酸磷酸化与 未鉴定的高分子量蛋白质的酪氨酸磷酸化， 与之相互作用。 该蛋白可能作为Shc的激活剂起作用 在应激过程中，启动Ras/ERK信号级联反应。 (2)应激反应中p90 RSK的激活及其与细胞凋亡的关系 IkB。 p90 RSK是一种丝氨酸/苏氨酸蛋白激酶，位于 ERK，因此被促有丝分裂刺激激活。 我们发现 p90 RSK可以被许多应激条件激活，包括亚砷酸盐， H2 O2和甲磺酸甲酯。 p90 RSK激活被发现， 与IkB的磷酸化和降解相关，IkB是一种抑制剂， 转录因子NF-κ B。 p90 RSK可以作为IkB激酶发挥作用， 在应激期间促进NF-κ B活化。 (3)EGF刺激的肝细胞中p70 S6 k的表达下降。 老化 与细胞增殖能力的下降有关。 以前我们发现这与ERK的减少有关， 通过促有丝分裂刺激激活。 我们现在已经注意到， p70 S6 k活性随年龄增长而显著下降。 因此，缺陷 在至少两个不同的信号转导途径可以解释 与年龄相关的增殖能力缺陷。上游分析 这两种途径共同的调节因子可以提供重要的见解 衰老的基本机制。