Mechanisms of Carcinogenesis

致癌机制

• 批准号: 7449218
• 负责人: DIANE E HECK
• 金额: $ 24.36万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-24 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7449218
• 关键词: 5-(4-hydroxy-3-methoxyphenyl)-5-phenylhydantoin; Antioxidants; Antisense Oligonucleotides; Azides; Biochemical; Calcium; Carcinogenesis Mechanism; Cell Nucleus; Cells; Chemicals; DNA Damage; DNA-Directed DNA Polymerase; Development; Down-Regulation; Drug Metabolic Detoxication; Enzymes; Epidermis; Event; Exposure to; Generations; Heating; Human; Hydrogen Peroxide; In Vitro; Light; Localized; Malignant Neoplasms; Mediating; Mediator of activation protein; Metabolic; Mitochondria; Modeling; Mono-S; Mus; Mutate; Oxidants; Oxidative Stress; Oxygen; Peroxidase; Peroxidases; Peroxides; Personal Satisfaction; Process; Production; Proteins; Range; Recombinants; Role; Sequence Analysis; Short Waves; Skin; Skin Cancer; Testing; Tissues; Transcription Factor AP-1; Transgenic Mice; Triazoles; UVB induced; Ultraviolet B Radiation; Ultraviolet Rays; Water; carcinogenesis; catalase; cell type; cytotoxic; keratinocyte; light treatment; oxidative DNA damage; peroxisome; reactive oxygen intermediate; repair enzyme; response; transcription factor; tumor

DESCRIPTION (provided by applicant): Exposure to ultraviolet light, in particular, ultraviolet light B (UVB, ultraviolet light in the wavelengths ranging from 290-320 nm) is known to be a major causative factor in the development of skin cancer. Epidermal cells express a variety of protective molecules that function by absorbing UVB light. Sun exposed tissue is also protected by detoxification and repair enzymes, as well as other antioxidant molecules. The precise mechanisms by which ultraviolet light induces tissue damage are not clear. It has been suggested that cytotoxic reactive oxygen intermediates generated by UVB light in the skin are responsible for causing DNA damage leading to cancer. We have discovered that UVB light rapidly stimulates the production of hydroperoxides by mouse and human keratinocytes in a process that does not require intact cells. Greater amounts of hydroperoxides are produced in calcium-differentiated keratinocytes when compared to growing keratinocytes. Purification studies using homogenates of keratinocytes identified a major protein responsible for generating hydrogen peroxide in the cells in response to UVB light. This UVB light/peroxide generating activity of requires oxygen and is eliminated by heat denaturation. Unexpectedly, sequence analysis identified this protein as catalase, an enzyme known to be responsible for the degradation of intracellular hydrogen peroxide. It is well recognized that catalase also possesses peroxidatic activity and UVB light stimulates this function of the enzyme. In this regard, we found that inhibition of the hydrogen peroxide metabolizing activity of catalase with 3-amino-1,2, 4-triazole or azide markedly enhanced the ability of UVB light to generate hydroperoxides. We hypothesize that catalase is an important mediator of UVB light-induced oxidative stress and DNA damage in keratinocytes. Our specific aims are to determine if catalase mediates ultraviolet light-induced oxidative stress and DNA damage in growing and differentiated keratinocytes and to evaluate the role of the enzyme in UVB-induced carcinogenesis using the mouse skin model. Our proposed studies will provide information on the mechanisms by which ultraviolet light induces DNA damage in the skin and should also provide information on the potential role of catalase in ultraviolet light induced skin cancer.

描述（申请人提供）：已知暴露于紫外线，特别是紫外线B（UVB，波长范围为290-320 nm的紫外线）是导致皮肤癌的主要致病因素。表皮细胞表达多种通过吸收 UVB 光发挥作用的保护分子。暴露在阳光下的组织也受到解毒和修复酶以及其他抗氧化剂分子的保护。紫外线引起组织损伤的确切机制尚不清楚。有人认为，UVB 光在皮肤中产生的细胞毒性活性氧中间体会导致 DNA 损伤，从而导致癌症。我们发现，UVB 光可快速刺激小鼠和人类角质形成细胞产生氢过氧化物，而这一过程不需要完整的细胞。与生长的角质形成细胞相比，钙分化的角质形成细胞产生更多的氢过氧化物。使用角质细胞匀浆进行的纯化研究确定了一种主要蛋白质，该蛋白质负责响应 UVB 光在细胞中产生过氧化氢。这种产生 UVB 光/过氧化物的活性需要氧气并通过热变性消除。出乎意料的是，序列分析发现这种蛋白质是过氧化氢酶，一种已知负责细胞内过氧化氢降解的酶。众所周知，过氧化氢酶也具有过氧化活性，UVB 光可以刺激酶的这种功能。在这方面，我们发现用3-氨基-1,2,4-三唑或叠氮化物抑制过氧化氢酶的过氧化氢代谢活性显着增强了UVB光产生氢过氧化物的能力。我们假设过氧化氢酶是 UVB 光诱导的角质形成细胞氧化应激和 DNA 损伤的重要介质。我们的具体目标是确定过氧化氢酶是否介导生长和分化的角质形成细胞中紫外线诱导的氧化应激和 DNA 损伤，并使用小鼠皮肤模型评估该酶在 UVB 诱导的癌变中的作用。我们提出的研究将提供有关紫外线诱导皮肤 DNA 损伤的机制的信息，并且还应提供有关过氧化氢酶在紫外线诱导的皮肤癌中潜在作用的信息。