Wiring the UV Signaling Circuitry

连接 UV 信号电路

• 批准号: 7473494
• 负责人: ANNING LIN
• 金额: $ 34.54万
• 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 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7473494
• 关键词: Affect; Apoptosis; Biochemical Genetics; Biological Models; Biological Process; Carcinogens; Cell Death; Cells; Cellular Stress; Cellular Stress Response; Cessation of life; Event; Family; Forms Controls; Goals; In Vitro; JUN gene; MAPK8 gene; Malignant Neoplasms; Mammalian Cell; Membrane; Molecular; N-terminal; NF-kappa B; Nature; Nuclear; Outcome; Pathway interactions; Phosphorylation; Physiological; Play; Prevention; Protein Kinase; Public Health; Radiation; Regulation; Research; Role; Signal Transduction; Skin Cancer; Stimulus; Stress; Testing; Thinking; Tyrosine Phosphorylation; design; human disease; in vivo; novel; novel strategies; p65; response; transcription factor; 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（由申请人提供）：我们的长期目标是了解控制细胞应激反应的分子机制，从而探索靶向细胞应激信号通路预防和治疗人类疾病的潜力。在本研究中，我们将研究应力信号网络的整合；即。“连接应力信号通路”，使用NF-kappaB和JNK1之间的串扰作为模型系统来调节UV信号。