This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Our preliminary data indicate that UV radiation up-regulates HIFIa and DEC1, both are involved in cell survival and proliferation. The signaling pathway leading to HIFIa and DEC1 expression is unknown. The hypotheses to be tested in this proposed project are that EGFR/Rac1/P13K/AKT mediates UV-induced HIF1a expression, and DEC1 and HIF1a are reciprocally regulated.
The specific aims of this project are: 1) To define the role of EGFR in UV-induced expression of HIF1a. (a) EGFR inhibitors and (b) Forced expression of EGFR (e.g. over-expression of EGFR, knockout of EGFR, RNAi) will be utilized to determine whether modulation of EGFR would affect the expression HIF1a and its target genes; 2) To determine the role of Rac1/P13K/AKT pathway in UV-induced expression of HIF1a (a) Rac1 and P13 kinase inhibitors and (b) Forced expression of Rac1 and P13 kinase (e.g. over-expression of P13 kinase subunits and Rac1, or dominant negative subunits of P13 kinase and Rac1) will be utilized to determine whether modulation of Rac1/P13 kinase signal would affect the expression of HIF1a; 3) To investigate whether DEC1 and HIF1a are reciprocally regulated in response to UV irradiation. (a) Forced expression of DEC1 (e.g. DEC1 knockout or RNAi, over-expression of DEC1) will be used to determine whether UV-induced HIF1a expression is DEC1-dependent. (b) Forced expression of HIFIa will be used to determine whether DEC1-dependent expression of HIF1a also transactivates DEC1. Our expectations are that, at the conclusion of this project, we will have: (a) delineated a novel cell signaling pathway in response to UV irradiation leading to the expression of HIF1a; and (b) a novel mechanism of reciprocal regulation of HIF1a and DEC1 in response to UV radiation. Overall, the experiments outlined will contribute significantly to our basic understanding of molecular mechanism of UV-induced skin photoaging and skin cancer, and provide molecular basis for developing preventive and therapeutic strategies.
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