Delta-Np63, a p53 family member commonly expressed in squamous cell carcinomas (SCC), may promote tumor growth by interfering with p53-dependent signaling. The first goal of this proposal is to demonstrate that delta-Np63 over-expression promotes cell growth and inhibits apoptosis in SCC cells. This will be accomplished by selectively blocking delta-Np63 expression using small interfering RNA, then examining both cell growth and proliferation and apoptotic response after DNA damage. The second goal of this proposal is to define promoter elements and transcription factors responsible for delta-Np63 over-expression expression in SCC cells. This will be accomplished by evaluating promoter activity of nested deltion delta- Np63 promoter-luciferase constructs in transiently transfected SCC cells. Delta-Np63 promoter elements responsible for down-regulation of delta-Np63 expression in response to ultraviolet radiation will also be identified by similar techniques. Electrophorectic mobility shift assays and chromatin immunoprecipitation assays will be used to analyze transcription factor binding at functionally defined delta-Np63 promoter elements. Definition of delta-Np63 signaling pathways may provide therapeutic targets in SCC. ? ? ? ?
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