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

诊断出100多万例非黑色素瘤皮肤癌和59,600例黑色素瘤 在美国，每年约有10,600人死亡(约7,800人死于黑色素瘤)。在……里面 近年来，紫外线损伤的皮肤有更多的机会发展为 各种类型的皮肤癌，包括基底细胞癌、鳞状细胞癌和皮肤恶性肿瘤 黑色素瘤。对紫外线的凋亡反应是一种保护性反应，它消除了接受高辐射的细胞 紫外线剂量。虽然大多数研究都集中在DNA损伤诱导的，P53依赖的紫外线诱导的通路 细胞凋亡、膜受体介导的信号通路也在诱导细胞凋亡中发挥重要作用 细胞凋亡。紫外线照射激活使真核生物起始的α亚基磷酸化的激酶 因子2(ElF2a)，随后抑制蛋白质合成。翻译在调节中起着重要的作用 细胞凋亡基因的表达。然而，导致elF2a激酶的上游信号通路(S)(S) 紫外线照射后的激活尚不清楚。 这项应用的目的是阐明通过一氧化氮调节紫外线诱导的细胞凋亡的机制 一氧化氮合酶(NOS)介导的信号转导途径及一氧化氮的作用 (NO)/过亚硝酸根(ONOO~)和锌(锌)在紫外线诱导的翻译调节和细胞凋亡中的作用。这个 在这项申请中提出的研究具有重要意义，因为了解一氧化氮合酶激活的调节 而这种调节如何影响紫外线照射下elF2a激酶(S)的激活和/或细胞凋亡，将导致 识别靶基因的新信号网络和预防治疗的发展 以及紫外线相关癌症的治疗。在特定的目标I中，我们建议阐明紫外线诱导和NO介导的 导致elF2ct磷酸化的信号通路(S)。工作假说是，没有 介导紫外线诱导的elF2a激酶(S)的激活，使elF2a磷酸化。在第二个具体目标中，我们 提出确定NO/ONOO“产生的机制和动力学及其在紫外线诱导中的作用 细胞凋亡。工作假说是，在NO：ONOO~的高比率下，紫外线的作用可以是抗凋亡的， 而在低比例的情况下，这种效应可能是促凋亡的。在具体目标三中，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(S)。工作假说是 在紫外线照射下，[Zn2]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信号通路的知识，但也将导致进一步的 对其他生理条件诱导的调节机制和信号通路的理解 (例如，再灌流、伤口愈合、糖尿病)，受NO和翻译抑制的影响。

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.