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.
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