Wiring the UV Signaling Circuitry

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用于预防和治疗人类疾病的潜力。在这个提议中，我们将研究压力信号网络的整合;即“布线压力信号电路”，使用NF-κ B和JNK 1之间的串扰对UV信号的调节作为模型系统。 使用遗传和生物化学方法，我们最近发现，转录因子NF-κ B，这是已知的细胞中的关键生存因子，令人惊讶的功能作为一个前死亡因子在紫外线诱导的细胞凋亡，通过促进激活c-Jun N-末端蛋白激酶1（JNK 1）。具体而言，RelA/p65是NF-κ B家族的主要反式激活亚基，以其预先存在的核形式控制非刺激细胞中蛋白激酶c δ（PKC δ）的表达。这种“引发”效应允许UV快速激活PKC δ，这是JNK 1和细胞死亡的快速和稳健激活所需的。我们假设NF-κ B和JNK 1之间的新串扰在程序性细胞死亡和肿瘤发生中的UV信号通路中是至关重要的。 这个提议是新颖的，因为它将确定NF-κ B-PKC δ轴调节UV诱导的JNK 1活化和细胞死亡的分子机制，阐明PKC δ参与UV信号通路整合的分子机制，并确定NF-κ B和JNK 1之间的新型串扰在体内响应物理应激的病理生理学相关性。 这项研究将提出一个新的范式，关于紫外线信号通路整合的分子机制，也将提供开发新的策略，用于预防和治疗与身体压力相关的人类疾病和癌症的理论基础。公共卫生相关性：紫外线（UV）是一种主要的物理压力，也是皮肤癌的完全致癌物。本研究旨在确定在生理和/或病理事件如程序性细胞死亡、凋亡和肿瘤发生中，两个主要细胞信号调节因子NF-：B和JNK 1之间的串扰如何“连接”紫外线照射的信息。这项研究将测试一种新的模式，关于紫外线信号电路整合的分子机制，也将提供开发新的策略，用于预防和治疗与身体压力相关的人类疾病和癌症的基本原理。

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.