Hypoxia-inducible factor1a in multistage carcinogenesis

多阶段癌变中的缺氧诱导因子1a

• 批准号: 6468665
• 负责人: Jeffrey Michael Arbeit
• 金额: $ 35.29万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6468665
• 关键词: carcinogenesis; cervix neoplasms; chemical carcinogenesis; estrogens; female; genetically modified animals; human papillomavirus; hypoxia inducible factor 1; laboratory mouse; neoplastic transformation; skin neoplasms; tissue /cell culture; tumor suppressor genes; viral carcinogenesis

DESCRIPTION (PROVIDED BY APPLICANT):Hypoxia inducible factor 1-alpha (HIF-1alpha) is a component of the transcription factor HIF-1. Cell culture studies and mouse gene knockouts demonstrate HIF-1alpha transactivation of genes controlling angiogenesis, cellular metabolism, invasion and apoptosis. In addition to hypoxia. HIF-1alpha protein expression is regulated by growth factor signaling and survival pathways, and viral oncogenes. HIF-1alpha expression is induced in cancers and high-grade premalignant lesions. However. HIF-1alpha function in each stage of epithelial carcinogenesis or metastasis is unknown. We created transgenic mice expressing either wild type or a constitutively active mutant HIF-1alpha lacking the "oxygen-dependent degradation domain' about in basal squamous epithelium (K14-HIF-1alpha and K14-HIF-1alpha delta ODD transgenic mice). We have engineered Cre-loxP mediated HIF-1a deletion in basal squamous epithelium without a discernable phenotype. Now we test whether HIF-1alpha plays a fundamental role in multistage epithelial carcinogenesis with these Specific Aims 1. Determine the stage-specific effect of gain or loss of HIF-1alpha function on Ha-ras initiated epidermal carcinogenesis. 1.1. Test whether gain of HIF- 1alpha function promotes two-stage epidermal chemical carcinogenesis induced by dimethylbenzanthracene and tetraphorbolmyristate acetate in Kl4-HIF-1alpha and Kl4-HIF-laz\ODD transgenic mice. 1.2. Test necessity of HIF-1alpha in two-stage chemical carcinogenesis in mice with Cre-loxP mediated epidermal HIF-1alpha deletion. 2.0. Determine biology of gain of HIF-1alpha function on multistage carcinogenesis in skin and cervix induced by the HPV16 early transforming region. 2.1. Test alteration of each stage of HPV16-induced epidermal carcinogenesis by gain of HIF-1alpha function in KI4-HPV16:HIF-1alpha or HIF-1alpha delta ODD double transgenic mice. 2.2. Test cooperation between HIF-1alpha gain of function and estrogen in HPV16 induced cervical carcinogenesis in mice transgenic for the HPV16 and HIF-1alpha or HIF-1alpha delta ODD. 3.0. Test biology of HPV16 E6-HIF-1alpha coexpression, and determine p53 dependent or independent functions of E6 in conjunction with HIF-1alpha. 3.1. Create Kl4-E6HIF-1alpha or K14-E6:HlF-1alpha delta ODD double transgenic mice and determine alterations in the biology of skin and cervical carcinogenesis. 3.2. Create Kl4-E6 HIF-1alpha or K14-E6:HIF-1alpha delta ODD double transgenic mice and determine alterations in the biology of skin and cervical carcinogenesis. Our possession of all relevant animal models, positions us to determine the precise role of HIF-1alpha in carcinogenesis mediated by either activated oncogenes or inactivation of tumor suppressor genes.

描述(申请人提供)：缺氧诱导因子1-α(HIF-1α) 是转录因子HIF-1的一个组成部分。细胞培养研究和 小鼠基因敲除显示HIF-1α控制基因的反式激活 血管生成、细胞代谢、侵袭和凋亡。除了……之外 缺氧。HIF-1α蛋白表达受生长因子信号转导和 生存途径和病毒致癌基因。HIF-1α在癌症中的诱导表达 和高度癌前病变。然而。缺氧诱导因子-1α在脑缺血再灌注损伤中的作用 上皮性癌的发生或转移尚不清楚。我们创造了转基因小鼠 表达野生型或结构性活性突变体HIF-1α缺失 基底层鳞状上皮中的“氧依赖降解结构域” (K14-HIF-1α和K14-HIF-1αβ转基因小鼠)。我们已经设计了 Cre-loxP介导的HIF-1a缺失型基底鳞状上皮 可辨别的表型。现在我们测试HIF-1α是否在 具有这些特定目的的多阶段上皮癌发生 1.确定HIF-1α功能的得失对细胞周期的影响 HA-ras启动了表皮癌变。1.1.检测HIF-1α的增益 功能促进小鼠皮肤化学致癌的两个阶段 KL4-HIF-1α和KL4-HIF-1α中的二甲基苯并菲和四氯肉豆蔻酸酯 KL4-HIF-laz转基因小鼠。1.2.缺氧诱导因子-1α两阶段试验的必要性 Cre-loxP介导的小鼠表皮HIF-1α化学致癌作用 删除。2.0版本。多阶段测定HIF-1α功能增益的生物学 HPV16早期转化诱导的皮肤和宫颈癌变 区域。2.1.人乳头瘤病毒16诱导的表皮各阶段的实验变化 KI4-HPV16中HIF-1α功能增强致癌：HIF-1α或HIF-1α Delta奇数双转基因小鼠。2.2.检测HIF-1α与HIF-1的协同作用 HPV16诱导小鼠宫颈癌发生过程中的作用及雌激素 HPV16和HIF-1α或HIF-1α的转基因为奇数。3.0。测试生物学 HPV16E6-HIF-1α共表达，并确定P53依赖或非依赖 E6与HIF-1α的协同作用。3.1.创建KL4-E6HIF-1pha或 K14-E6：HLF-1αβ奇数双转基因小鼠 皮肤生物学和子宫颈癌变。3.2.创建KL4-E6 HIF-1α或 K14-E6：HIF-1αβ奇数双转基因小鼠 皮肤生物学和子宫颈癌变。我们拥有所有相关的 动物模型，使我们能够确定HIF-1α在 癌基因激活或肿瘤失活介导的致癌作用 抑制基因。