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UV-induced and NOS-mediated Zn elevation, translation regulation and apoptosis

UV 诱导和 NOS 介导的 Zn 升高、翻译调节和细胞凋亡

基本信息

批准号：
8298670
负责人：
Shiyong Wu
金额：
$ 25.44万
依托单位：
OHIO UNIVERSITY ATHENS
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-09-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8298670
关键词：
Affect Apoptosis Apoptotic Basal cell carcinoma Biological Availability Cell Death Cell Death Inhibition Cells Cessation of life Cutaneous Melanoma DNA Damage Data Development Diabetes Mellitus Diagnosis Dose Dose-Rate EIF-2alpha Environment Event Gene Expression Gene Targeting Generations Goals Health In Situ Kinetics Knowledge Lead Life Malignant Neoplasms Measures Mediating Membrane Molecular Monitor Nanotechnology Nitric Oxide Nitric Oxide Synthase Outcome Outcome Study Outcomes Research Pathway interactions Peroxonitrite Phosphorylation Phosphotransferases Physiological Play Prevention Production Protein Biosynthesis Qualifying Regulation Reperfusion Therapy Reporting Research Role Signal Pathway Signal Transduction Skin Skin Aging Skin Cancer Skin Carcinoma Squamous cell carcinoma Staging Stress Superoxides System Testing Therapeutic Time Translations Ultraviolet Rays United States Work Wound Healing Zinc base cell injury design innovation irradiation melanoma nanosensors novel novel therapeutics prevent receptor-mediated signaling response therapeutic development

项目摘要

DESCRIPTION (provided by applicant): 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 UV-induced 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 (eIF21) 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 eIF21 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 eIF21 kinase(s) activation and/or apoptosis upon UV-irradiation will lead us 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 proposed to elucidate the UV-induced and NO-mediated signaling pathway(s) that leads to eIF21 phosphorylation. The working hypothesis is that NO mediates UV-induced activations of eIF21 kinase(s), which phosphorylate eIF21. In Specific Aim II: we proposed 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 anti-apoptotic, while at a low ratio this effect can be pro-apoptotic. In Specific Aim III, we proposed 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 multiple 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. PUBLIC HEALTH RELEVANCE: Cell death induced by ultraviolet light (UV) is a protective response that eliminates damaged cells. In the proposal, we will study the mechanisms that regulate UV-induced apoptosis via nitric oxide synthase mediated signaling pathways and to determine the roles of nitric oxide/peroxynitrite and cytosolic zinc concentration in UV-induced translation regulation and apoptosis. The outcomes from these studies will not only increase our knowledge of UV- induced multiple apoptotic signaling pathways, but will also lead us to the development of new therapeutics for treatment of UV-related skin aging and cancers.

描述（由申请人提供）：美国每年诊断出超过 100 万例非黑色素瘤皮肤癌和 59,600 例黑色素瘤病例，2005 年导致约 10,600 人死亡（其中约 7,800 人死于黑色素瘤）。近年来，已经清楚的是，受紫外线损伤的皮肤患上其中一种皮肤癌的机会增加，包括基底细胞癌、鳞状细胞癌和皮肤癌。皮肤的恶性黑色素瘤。对紫外线的凋亡反应是一种保护性反应，可以消除接受高剂量紫外线的细胞。虽然大多数研究都集中在 UV 诱导的细胞凋亡的 DNA 损伤诱导、p53 依赖性途径上，但膜受体介导的信号传导途径在诱导细胞凋亡中也发挥着重要作用。紫外线照射会激活激酶，使真核起始因子 2 (eIF21) 的 α 亚基磷酸化，从而抑制蛋白质合成。翻译在凋亡基因表达的调控中发挥着重要作用。然而，在紫外线照射下导致 eIF21 激酶激活的上游信号通路尚不清楚。本申请的目的是阐明通过一氧化氮合酶 (NOS) 介导的信号通路调节紫外线诱导的细胞凋亡的机制，并确定一氧化氮 (NO)/过氧亚硝酸盐 (ONOO) 和锌 (Zn2+) 在紫外线诱导的翻译调节和细胞凋亡中的作用。本申请中提出的研究意义重大，因为了解 NOS 激活的调节以及这种调节如何影响 UV 照射后 eIF21 激酶的激活和/或凋亡，将引导我们找到一个新的信号网络，用于识别靶基因并开发预防和治疗 UV 相关癌症的疗法。在特定目标 I 中，我们建议阐明导致 eIF21 磷酸化的 UV 诱导和 NO 介导的信号通路。目前的假设是，NO 介导紫外线诱导的 eIF21 激酶激活，从而磷酸化 eIF21。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紫外线诱导的细胞凋亡中的作用。工作假设是，在高比例的 NO:ONOO 下，紫外线的作用可以是抗凋亡的，而在低比例的情况下，这种作用可以是促凋亡的。在特定目标 III 中，我们建议确定 Zn 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+] 在紫外线照射下介导 NO 诱导的细胞凋亡。这项研究的结果不仅将增加我们对紫外线诱导和一氧化氮合酶介导的多种信号通路的了解，还将进一步了解受一氧化氮和翻译抑制影响的其他生理条件（例如再灌注、伤口愈合、糖尿病）诱导的调节机制和信号通路。公共健康相关性：紫外线 (UV) 诱导的细胞死亡是一种消除受损细胞的保护性反应。在该提案中，我们将研究通过一氧化氮合酶介导的信号通路调节紫外线诱导的细胞凋亡的机制，并确定一氧化氮/过氧亚硝酸盐和胞质锌浓度在紫外线诱导的翻译调节和细胞凋亡中的作用。这些研究的结果不仅将增加我们对紫外线诱导的多种细胞凋亡信号通路的了解，还将引导我们开发出治疗紫外线相关皮肤老化和癌症的新疗法。

项目成果

期刊论文数量（39）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Effects of nitric oxide-releasing nonsteroidal anti-inflammatory drugs (NONO-NSAIDs) on melanoma cell adhesion.

DOI：
10.1016/j.taap.2012.07.029
发表时间：
2012-10-15
期刊：
TOXICOLOGY AND APPLIED PHARMACOLOGY
影响因子：
3.8
作者：
Cheng, Huiwen;Mollica, Molly Y.;Lee, Shin Hee;Wang, Lei;Velazquez-Martinez, Carlos A.;Wu, Shiyong
通讯作者：
Wu, Shiyong

Nitric oxide: a regulator of eukaryotic initiation factor 2 kinases.