Wiring the UV Signaling Circuitry

连接 UV 信号电路

• 批准号: 8228071
• 负责人: ANNING LIN
• 金额: $ 33.85万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-08 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8228071
• 关键词: Address; Anesthesia procedures; Apoptosis; Apoptotic; Biochemical; Biological Models; Carcinogens; Cell Death; Cells; Cellular Stress; Cellular Stress Response; Cessation of life; Data; Dorsal; Dose; Event; Experimental Designs; Family; Figs - dietary; Forms Controls; Genetic; Goals; Harvest; Health; Human; In Vitro; Inbred HRS Mice; JUN gene; Letters; MAPK8 gene; Malignant Neoplasms; Molecular; Mus; N-terminal; NF-kappa B; Nuclear; Pathway interactions; Physiological; Prevention; Protein Kinase; Radiation; Regulation; Reporting; Research; Role; Signal Transduction; Singapore; Skin; Skin Cancer; Skin Neoplasms; Stimulus; Stress; Suggestion; Testing; Time; UV induced; UVB induced; Ultraviolet B Radiation; Universities; Utah; Writing; base; cell type; design; human disease; in vivo; irradiation; keratinocyte; killings; novel; novel strategies; p65; research study; response; transcription factor; tumor; tumorigenesis; ultraviolet; ultraviolet irradiation

DESCRIPTION (provided by applicant): Our long-term goal is to understand the molecular mechanisms that govern the cellular stress response, thereby exploring the potential of targeting the cellular stress signaling circuitry for prevention and treatment of human diseases. In this proposal, we will study the integration of the stress signaling network; i.e. "wiring the stress signaling circuitry", using the regulation of UV signaling by the crosstalk between NF-kappaB and JNK1 as a model system. Using both genetic and biochemical approaches, we recently found that the transcription factor NF-kappaB, which is known as a key survival factor in cells, surprisingly functions as a pro-death factor in UV-induced apoptosis by promoting activation of c-Jun N-terminal protein kinase 1 (JNK1). Specifically, RelA/p65, which is a major transactivating subunit of the NF-kappaB family, in its pre-existing nuclear form controls expression of protein kinase c delta (PKCdelta) in non-stimulated cells. This "priming" effect allows UV to quickly activate PKCdelta, which is required for rapid and robust activation of JNK1 and cell death. We hypothesize that the novel crosstalk between NF-kappaB and JNK1 is critical in "wiring" the UV signaling circuitry in programmed cell death and tumorigenesis. This proposal is novel, as it will determine the molecular mechanism by which the NF-kappaB-PKCdelta axis regulates UV-induced JNK1 activation and cell death, to elucidate the molecular mechanism by which PKCdelta participates in the integration of the UV signaling circuitry, and to determine the pathophysiological relevance of the novel crosstalk between NF-kappaB and JNK1 in response to physical stress in vivo. This study will put forward a novel paradigm regarding the molecular mechanism by which the UV signaling circuitry is integrated and will also provide the rationale in developing novel strategies for prevention and treatment of physical stress-related human diseases and cancer. PUBLIC HEALTH RELEVANCE: Ultraviolet (UV) is a major physical stress and is also a complete carcinogen in skin cancer. This research is designed to determine how the information of UV-irradiation is "wired" by the crosstalk between two major cell signaling regulators, NF-:B and JNK1 in physiological and/or pathological events such as programmed cell death apoptosis and tumorigenesis. This study will test a novel paradigm regarding the molecular mechanism by which the UV signaling circuitry is integrated and will also provide the rationale in developing novel strategies for prevention and treatment of physical stress-related human diseases and cancer.

描述(申请人提供)：我们的长期目标是了解支配细胞应激反应的分子机制，从而探索以细胞应激信号通路为靶点预防和治疗人类疾病的可能性。在这个方案中，我们将研究胁迫信号网络的整合，即“连接胁迫信号电路”，以NF-kappaB和JNK1之间的串扰对UV信号的调节为模型系统。 我们最近利用遗传学和生物化学的方法发现，转录因子NF-kappaB作为细胞中的关键生存因子，通过促进c-jun氨基末端蛋白激酶1(JNK1)的激活，在紫外线诱导的细胞凋亡中发挥着令人惊讶的促死亡因子的作用。具体地说，作为核转录因子-kappaB家族的主要反式激活亚单位，relA/p65以其原有的核形式控制着未受刺激的细胞中蛋白激酶C增量(PKCDelta)的表达。这种“启动”效应允许紫外线快速激活PKCDelta，这是快速而有力地激活JNK1和细胞死亡所必需的。我们推测，核因子-kappaB和JNK1之间的新的串扰在程序性细胞死亡和肿瘤发生的紫外线信号电路中是关键的。 这一建议是新颖的，因为它将确定NF-kappaB-PKCDelta轴调节紫外线诱导的JNK1激活和细胞死亡的分子机制，阐明PKCDelta参与UV信号通路整合的分子机制，并确定新的NF-kappaB和JNK1之间的串扰在体内响应物理应激的病理生理学相关性。 这项研究将提出一种关于紫外线信号通路整合的分子机制的新范式，并将为开发预防和治疗与身体应激相关的人类疾病和癌症的新策略提供理论基础。与公众健康相关：紫外线(UV)是一种主要的身体压力，也是皮肤癌的完全致癌物。这项研究旨在确定紫外线辐射的信息是如何通过两个主要的细胞信号调节因子NF-：B和JNK1在生理和/或病理事件(如程序性细胞死亡、细胞凋亡和肿瘤发生)之间的串扰而被连接起来的。这项研究将测试一种关于紫外线信号电路整合的分子机制的新范例，并将为开发预防和治疗与身体应激相关的人类疾病和癌症的新策略提供理论基础。