UV-induced and NOS-mediated Zn elevation, translation regulatin and apoptosis.

UV 诱导和 NOS 介导的 Zn 升高​​、翻译调节和细胞凋亡。

• 批准号: 7483439
• 负责人: Shiyong Wu
• 金额: $ 20.64万
• 依托单位: OHIO UNIVERSITY ATHENS
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7483439
• 关键词: Affect; Apoptosis; Apoptotic; Arginine; Basal cell carcinoma; Biological Availability; Cell Death; Cell Death Inhibition; Cell Death Signaling Process; Cells; Cessation of life; Collaborations; Condition; Cultured Cells; Cutaneous Melanoma; DNA Damage; Data; Detection; Development; Devices; Diabetes Mellitus; Diagnosis; Dose; EIF-2alpha; Elevation; Endoplasmic Reticulum; Environment; Event; Gene Expression; Gene Targeting; Generations; Goals; In Situ; Kinetics; Knowledge; Laboratories; Lead; Life; Malignant Neoplasms; Measures; Mediating; Membrane; Molecular; Monitor; NF-kappa B; Nanotechnology; Nitric Oxide; Nitric Oxide Synthase; Outcome; Outcomes Research; Pathway interactions; Peroxonitrite; Phase; Phosphorylation; Phosphotransferases; Physiological; Physiological reperfusion; Play; Prevention; Production; Protein Biosynthesis; Qualifying; Regulation; Reperfusion Therapy; Reporting; Research; Role; Role playing therapy; Signal Pathway; Signal Transduction; Skin; Skin Cancer; Skin Carcinoma; Staging; Stress; Superoxides; System; Testing; Therapeutic; Time; Translational Repression; Translations; Ultraviolet Rays; United States; Work; Wound Healing; Zinc; base; cell injury; cofactor; concept; deprivation; design; inhibitor/antagonist; innovation; irradiation; melanoma; nanosensors; novel; prevent; receptor; response; skin squamous cell carcinoma; small molecule

More than 1 million cases of nonmelanoma skin cancer and 59,600 cases of melanoma are diagnosed yearly in the United States, resulting in about 10,600 deaths (about 7,800 due to melanoma) in 2005. In recent years it has become clear that UV-damaged skin has an increased chance of developing one of the forms of skin cancer, including basal cell carcinoma, squamous cell carcinoma and cutaneous malignant melanoma. The apoptotic response to UV is a protective response that eliminates cells that receive high doses of UV. While most studies have focused on DNA damage-inducible, p53-dependent pathways of UVinduced apoptosis, membrane receptor mediated signaling pathways also play an important role in inducing apoptosis. UV-irradiation activates kinases that phosphorylate the alpha subunit of eukaryotic initiation factor 2 (elF2a ) and subsequently inhibit protein synthesis. Translation plays an important role in regulation of apoptotic gene expression. However, the upstream signaling pathway(s) that leads to elF2a kinase(s) activation upon UV-irradiation is not known. The objective of this application is to elucidate the mechanisms that regulate UV-induced apoptosis via nitric oxide synthase (NOS) mediated signaling pathways and to determine the roles of nitric oxide (NO)/peroxynitrite (ONOO~) and zinc (Zn2+) in UV-induced translation regulation and apoptosis. The research proposed in this application is significant because understanding the regulation of NOS activation and how this regulation affects elF2a kinase(s) activation and/or apoptosis upon UV-irradiation will lead to a new signaling network for identification of target genes and development of therapeutics in the prevention and treatment of UV-related cancers. In Specific Aim I, we propose to elucidate the UV-induced and NOmediated signaling pathway(s) that leads to elF2ct phosphorylation. The working hypothesis is that NO mediates UV-induced activation of elF2a kinase(s), which phosp_horylate elF2a . In Specific Aim II, we propose to determine the mechanism and kinetics of NO/ONOO" production and their role in UV-induced apoptosis. The working hypothesis is that at a high ratio of NO:ONOO~, the effect of UV can be antiapoptotic, while at a low ratio this effect can be pro-apoptotic. In Specific Aim III, we propose to determine the role(s) of Zn in UV-induced ER-stress and apoptotic signaling pathways. The working hypothesis is that [Zn2+] mediates NO-induced apoptosis upon UV-irradiation. The outcomes from this research will not only increase our knowledge of UV-induced and NOS-mediated signaling pathways, but will also lead to a further understanding of regulatory mechanisms and signaling pathways induced by other physiological conditions (e.g., reperfusion, wound healing, diabetes) that are affected by NO and translation inhibition.

超过100万例非黑色素瘤皮肤癌和59，600例黑色素瘤被诊断 在美国，每年有约10，600例死亡（约7，800例死于黑色素瘤）。在 近年来，很明显，紫外线损伤的皮肤有一个发展的机会增加，其中之一， 各种形式的皮肤癌，包括基底细胞癌、鳞状细胞癌和皮肤恶性肿瘤 黑素瘤对紫外线的凋亡反应是一种保护性反应， 紫外线剂量。虽然大多数研究都集中在DNA损伤诱导，p53依赖的途径紫外线诱导的 膜受体介导的信号通路也在诱导细胞凋亡中起重要作用 凋亡紫外线照射激活磷酸化真核生物起始的α亚基的激酶 因子2（eIF 2a）并随后抑制蛋白质合成。翻译在监管中起着重要作用 凋亡基因的表达。然而，导致eIF 2a激酶的上游信号传导途径 紫外线照射时的活化是未知的。 本申请的目的是阐明调节紫外线诱导的细胞凋亡的机制，通过一氧化氮 氧化合酶（NOS）介导的信号通路并确定一氧化氮的作用 (NO)/过氧亚硝基阴离子（ONOO~-）和锌（Zn ~（2+））在紫外线诱导的翻译调节和细胞凋亡中的作用。的 本申请中提出的研究是有意义的，因为了解NOS激活的调节 以及这种调节如何影响eIF 2a激酶的激活和/或UV照射后的细胞凋亡将导致 用于鉴定靶基因和开发预防中的治疗剂的新信号传导网络 和治疗与紫外线有关的癌症。在具体目标I中，我们建议阐明UV诱导的和NO介导的 导致eIF 2ct磷酸化的信号传导途径。工作假设是，没有 介导UV诱导的eIF 2a激酶的活化，其磷酸化eIF 2a。在具体目标II中，我们 建议确定NO/ONOO”产生的机制和动力学及其在UV诱导的 凋亡工作假设是，在高NO：ONOO-比率下，UV的作用可以是抗凋亡的， 而在低比率下，这种作用可以是促凋亡的。在具体目标III中，我们建议确定 锌在紫外线诱导的内质网应激和细胞凋亡信号通路中的作用。工作假设是， [Zn2+]介导NO诱导的细胞凋亡。这项研究的结果不仅将 增加了我们对UV诱导和NOS介导的信号通路的了解，但也将导致进一步的 了解其他生理条件诱导的调节机制和信号通路 (e.g.,再灌注、伤口愈合、糖尿病），其受到NO和翻译抑制的影响。