ENVIROMENTAL STRESS AGENTS AND SIGNAL TRANSDUCTION

皮肤暴露在紫外线辐射和环境中 产生氧化损伤的有毒化合物对健康有许多负面影响 后果，其中皮肤癌的发展是最严重的之一 说真的。这些药物与表皮相互作用的机制和 表皮细胞如何对损伤做出反应尚不完全清楚。的 最令人感兴趣的是感受到损伤的细胞分子的身份 环境应激源，细胞内的信号通路，通过它 损伤是传递的，而决定细胞如何在 生存与死亡。在前一个赠款周期内，申请者确定 核糖体28S rRNA作为应激反应的分子传感器 紫外线B辐射和其他有毒分子。来自核糖体的信号是 通过激活应激激活蛋白的途径快速传递 激酶(SAPK)，似乎参与了许多关键的途径， 决定存活率或凋亡率。产生氧化损伤的物质不会 通过28S rRNA介导胁迫信号，而不是紫外线B或C辐射 通过诱导细胞内的氧化应激来激活SAPK(JNK和p38MAPK)。 最近，申请人发现，在原代正常角质形成细胞中 亚砷酸盐，一种氧化应激源， 或紫外线B辐射导致立即和坐标 ERK的去磷酸化和失活--一个新出现的激酶家族成员 参与细胞增殖和存活的调节。这个 申请者的证据表明ERK的快速去磷酸化结果 来自压力诱导的一种预先存在的磷酸酶的激活。的目标是 这一新的应用是为了鉴定角质形成细胞中的磷酸酶 负责中波紫外线对ERK的去磷酸化反应 辐射和亚砷酸盐，并确定调节的模式 应激激活的ERK磷酸酶。申请者还将决定是否 SAPK信号级联的成员负责激活 ERK磷酸酶。最后，他们建议阐明JNK、p38 MAP、 和ERK在角质形成细胞的凋亡和存活反应中的作用 紫外线B辐射和氧化应激。

Exposure of the skin to ultraviolet radiation and to environmental toxic compounds that produce oxidative damage have numerous negative health consequences, among which the development of skin cancer is one of the most serious. The mechanisms by which these agents interact with the epidermis and by which the epidermal cells respond to damage are incompletely understood. Of crucial interest is the identity of cellular molecules that sense damage from environmental stressors, the intracellular signaling pathways by which the damage is conveyed, and the mechanisms that determine how cells choose between survival and death. During the previous grant cycle the applicant identified the 28S rRNA of ribosomes as a molecular sensor for stress induced by ultraviolet B radiation and other toxic molecules. Signals from ribosomes are quickly conveyed through pathways that activate the stress-activated protein kinases (SAPK) and appear to be involved in many of the crucial pathways that determine survival or apoptosis. Agents that produce oxidative damage do not mediate stress signals via 28S rRNA, and neither ultraviolet B or C radiation activates the SAPK (JNK and p38 MAPK) by inducing oxidative stress in cells. Recently the applicants have discovered that in primary normal keratinocytes the activation of the SAPK cascade by either arsenite, an oxidative stressor, or ultraviolet B radiation leads to an immediate and coordinate dephosphorylation and inactivation of ERK, a kinase family member that appears to be involved in regulation of cell proliferation and survival. The applicants' evidence indicates that the rapid dephosphorylation of ERK results from a stress-induced activation of a pre-existing phosphatase. The aims of this renewal application are to identify in keratinocytes the phosphatase responsible for the dephosphorylation of ERK in response to ultraviolet B radiation and arsenite and to identify the mode of regulation of the stress-activated ERK phosphatase. The applicants will also determine whether members of the SAPK signaling cascade are responsible for the activation of the ERK phosphatase. Finally, they propose to elucidate the roles of JNK, p38 MAP, and ERK in apoptotic and prosurvival responses of human keratinocytes to ultraviolet B radiation and oxidative stress.