Interaction Between DJ-1 and TSC1-TSC2/TOR Signaling in Cell Survival

描述(申请人提供)：结节性硬化症(TSC)是一种人类综合征，其特征是多种组织中的良性肿瘤广泛发展，大脑中的病变会导致最令人衰弱的症状，如癫痫发作和智力低下。TSC1或TSC2肿瘤抑制基因的胚系突变导致了这种综合征。最近对果蝇的遗传学研究和哺乳动物细胞的生化研究表明，TSC1和TSC2负性调节雷帕霉素(TOR)信号通路的靶点，以控制细胞生长。因此，TOR信号的异常激活可能是TSC和其他良性肿瘤综合征发病的基础。Tor信号似乎是协调细胞生长和存活与能量和营养条件的关键整合点。不同的环境或生理信号进入TSC/TOR信号通路以控制细胞生长和存活的分子机制知之甚少。在我们对与家族性帕金森病相关的人类DJ-1基因的果蝇同源物的初步研究中，我们发现DJ-1A的抑制会导致TOR信号的受损和细胞死亡，并且DJ-1A在基因上与TSC/TOR途径的某些成分相互作用，促进细胞存活。这些结果表明DJ-1A是一种新的TSC/TOR信号调节因子。这一建议的目的是从机制上理解DJ-1A和TSC/TOR通路在促进细胞存活方面的相互作用。拟议的遗传和生化分析将为TSC/TOR信号的调控和功能提供新的见解。沿着这一方向的进一步研究可能会巩固TSC/TOR信号在促进病理条件下细胞存活方面的基础作用。这些研究可能在TSC和帕金森病的发病机制中涉及一种共同的生化途径，并为阐明导致TSC患者脑损害发生的分子事件提供了一条途径。进一步的研究可能导致新的治疗靶点的确定，并最终帮助开发针对TSC脑损伤的合理的基于机制的治疗策略。 这些研究可能在TSC和帕金森病的发病机制中涉及一种共同的途径。进一步的研究可能导致确定新的治疗靶点，并最终帮助开发基于机制的治疗策略，针对导致该病最具破坏性症状的TSC脑损伤。

DESCRIPTION (provided by applicant): Tuberous sclerosis complex (TSC) is a human syndrome characterized by widespread development of benign tumors in multiple tissues, with lesions in the brain causing the most debilitating symptoms such as seizures and mental retardation. Germline mutations in either TSC1 or TSC2 tumor suppressor genes cause this syndrome. Recent genetic studies in Drosophila and biochemical studies in mammalian cells have suggested that TSC1 and TSC2 negatively regulate the target of rapamycin (TOR) signaling pathway to control cell growth. Abnormal activation of TOR signaling may thus underlie the pathogenesis of TSC and other benign tumor syndromes. TOR signaling appears to serve as a crucial integration point that coordinates cell growth and survival with energy and nutrient conditions. Little is known about the molecular mechanisms by which diverse environmental or physiological signals feed into the TSC/TOR signaling pathway to control cell growth and survival. In our preliminary studies of a Drosophila homologue of human DJ-1 gene, which is associated with familial Parkinson's disease, we have found that inhibition of DJ-1A leads to impaired TOR signaling and cell death and that DJ-1A genetically interacts with certain components of TSC/TOR pathway to promote cell survival. These results implicate DJ-1A as a novel regulator of TSC/TOR signaling. The goal of this proposal is to achieve a mechanistic understanding of the interaction between DJ-1A and the TSC/TOR pathway in promoting cell survival. The proposed genetic and biochemical analyses will provide novel insights into the regulation and function of TSC/TOR signaling. Further studies along this direction could solidify a fundamental role for TSC/TOR signaling in promoting cell survival under pathological conditions. These studies could implicate a common biochemical pathway in the pathogenesis of TSC and Parkinson's disease and offer one avenue for elucidating the molecular events that cause the development of brain lesions in TSC patients. Further studies could lead to the identification of new therapeutic targets and ultimately help develop rational mechanism-based treatment strategies that target TSC brain lesions. These studies could implicate a common pathway in the pathogenesis of TSC and Parkinson's disease. Further studies could lead to the identification of new therapeutic targets and ultimately help develop mechanism-based treatment strategies that target TSC brain lesions which cause the most devastating symptoms of the disease.