ENVIROMENTAL STRESS AGENTS AND SIGNAL TRANSDUCTION
ENVIROMENTAL STRESS AGENTS AND SIGNAL TRANSDUCTION
批准号:
6635478
负责人:
BRUCE E. MAGUN
金额:
$37.75万
依托单位国家:
美国
项目类别:
财政年份:
1996
资助国家:
美国
项目状态:
已结题
起止时间:
1996-12-01 至 2006-02-28
关键词:
JUN kinase antisense nucleic acid apoptosis arsenic biological signal transduction cell growth regulation cysteine endopeptidases environmental stressor enzyme activity fibroblasts gene induction /repression genetically modified animals keratinocyte laboratory mouse microtubule associated protein mitogen activated protein kinase oxidative stress phosphoprotein phosphatase radiobiology transcription factor ultraviolet radiation
中文摘要
皮肤暴露于紫外线辐射和环境
产生氧化损伤的有毒化合物对健康有许多负面影响,
其中,皮肤癌的发展是最严重的后果之一。
认真的这些药物与表皮相互作用的机制,
表皮细胞对损伤的反应机制尚不完全清楚。的
至关重要的兴趣是细胞分子的身份,
环境压力源,细胞内信号传导途径,
损伤被传递,以及决定细胞如何在
生存和死亡在上一个赠款周期,申请人确定
核糖体28SrRNA作为应激分子传感器
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迅速传递
激酶(SAPK),并似乎参与许多关键途径,
决定存活或凋亡。产生氧化损伤的物质不会
通过28 S rRNA介导胁迫信号,而紫外线B或C辐射
通过诱导细胞中的氧化应激激活SAPK(JNK和p38 MAPK)。
最近,申请人发现在原代正常角质形成细胞中,
通过亚砷酸盐,一种氧化应激物,
或紫外线B辐射导致了一个直接的和协调的
ERK是一种激酶家族成员,
参与调节细胞增殖和存活。的
申请人的证据表明ERK的快速去磷酸化导致
来自于压力诱导的磷酸酶激活。的目的
该更新申请是鉴定角质形成细胞中的磷酸酶,
负责ERK对紫外线B应答的去磷酸化
辐射和亚砷酸盐,并确定调节模式,
应激激活ERK磷酸酶。申请人还将确定是否
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在人角质形成细胞凋亡和促生存反应中的作用
紫外线B辐射和氧化应激。
英文摘要
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.
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