Mechanisms of Carcinogenesis

致癌机制

• 批准号: 7390356
• 负责人: DIANE E HECK
• 金额: $ 24.03万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 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 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7390356
• 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)：暴露在紫外线下，特别是紫外线B(UVB，波长在290-320纳米之间的紫外线)是已知的皮肤癌发展的主要诱因。表皮细胞表达多种保护分子，通过吸收UVB光发挥作用。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。紫外线导致组织损伤的确切机制尚不清楚。有研究表明，紫外线在皮肤中产生的细胞毒性活性氧中间体是导致DNA损伤并导致癌症的原因。我们已经发现，UVB光可以快速刺激小鼠和人类角质形成细胞产生过氧化氢，这一过程不需要完整的细胞。与生长中的角质形成细胞相比，钙化角质形成细胞产生更多的过氧化氢。利用角质形成细胞匀浆进行的纯化研究发现，一种主要蛋白质负责在细胞中产生过氧化氢，以响应UVB光。的这种UVB光/过氧化氢产生活性需要氧气，并通过热变性消除。出乎意料的是，序列分析确定这个蛋白质是过氧化氢酶，一种已知负责降解细胞内过氧化氢的酶。众所周知，过氧化氢酶也具有过氧化活性，而UVB光可以刺激该酶的这一功能。在这方面，我们发现用3-氨基-1，2，4-三氮唑或叠氮抑制过氧化氢酶的代谢活性显著增强了UVB光产生过氧化氢的能力。我们推测，过氧化氢酶是UVB光诱导的氧化应激和角质形成细胞DNA损伤的重要中介。我们的具体目标是确定过氧化氢酶是否介导紫外线诱导的生长和分化角质形成细胞的氧化应激和DNA损伤，并使用小鼠皮肤模型评估过氧化氢酶在紫外线诱导的致癌中的作用。我们提出的研究将提供关于紫外线诱导皮肤DNA损伤的机制的信息，也应该提供关于过氧化氢酶在紫外线诱导皮肤癌中的潜在作用的信息。