Wiring the UV Signaling Circuitry

连接 UV 信号电路

• 批准号: 8039085
• 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 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8039085
• 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（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力信号传导回路以预防和治疗人类疾病的潜力。在此提案中，我们将研究应力信号网络的整合；即，使用NF-kappab和JNK1之间的串扰对紫外线信号的调节，将“应力信号传导电路接线”。 使用遗传和生化方法，我们最近发现，被称为细胞中的关键存活因子的转录因子NF-kappab令人惊讶地作为紫外线诱导的凋亡中的促凋亡，通过促进C-Jun N末端蛋白激酶1的激活（JNK1）。具体而言，Rela/p65是NF-kappab家族的主要反式激活亚基，其先前存在的核形式控制着蛋白激酶C三角洲（PKCDELTA）在未刺激的细胞中的表达。这种“启动”效果使紫外线可以快速激活PKCDELTA，这是JNK1和细胞死亡的快速而强大的激活所必需的。我们假设NF-kappab和JNK1之间的新型串扰在“接线”程序性细胞死亡和肿瘤发生中的UV信号通路至关重要。 该提议是新颖的，因为它将确定NF-kappab-Pkcdelta轴调节UV诱导的JNK1激活和细胞死亡的分子机制，以阐明PKCDELTA参与紫外线信号电路的整合，并确定pkcdelta的分子机制，并确定Neksigy the Nemply Crossk inf the Nemply ossigys inf的病理学效果。体内压力。 这项研究将提出一个关于紫外线信号通路的分子机制的新范式，并将为制定预防和治疗与身体压力相关的人类疾病和癌症的新型策略提供基本原理。公共卫生相关性：紫外线（UV）是一种主要的身体压力，也是皮肤癌中的完全致癌物。这项研究旨在确定两个主要的细胞信号调节剂之间的串扰信息如何“连接”紫外线 - nf-：b：b：b和jnk1在生理和/或病理事件中，例如编程细胞死亡凋亡和肿瘤发生。这项研究将测试有关紫外线信号通路的分子机制的新范式，并将为制定预防和治疗与身体压力相关的人类疾病和癌症的新型策略提供基本原理。