As the literature and our own results have shown, p53 is an important factor in the control of proliferation and induction of apoptosis. Interferon-beta (IFNb) has an important role in the modulation of the immune response, participates in the creation of anti-tumor immunologic memory and also impacts the proliferative and apoptotic potential of tumor cells. Recently, data from the literature has shown that IFNb activates transcription of p53 and that various components of the IFN system carry out their function utilizing the p53/p14arf pathway. In this project, we plan to evaluate the role of p53 in the effect of IFNb in a melanoma model. We constructed adenoviral vectors carrying the cDNAs for p53 or IFNb and we will initiate our studies with the production and characterization of viral stocks, AdCMVp53 and AdCMVIFNb. The anti-tumor effect of these viruses will be evaluated in the B16 cell line containing an shRNA for EGFP (as a negative control) or p53 (to diminish endogenous p53 expression). The activity of the transgenes will be measured with cell proliferation or death assays. For IFNb, we will seek alteration in target gene expression of the IFN system in presence or absence of p53. Similarly, we will seek alterations in p53 target gene expression after treatment with IFNb. We expect to observe that the combination of p53 plus IFNb will be more efficient than either gene alone in the inhibition of proliferation, induction of cell death and activation of target gene expression. This project will serve as the base for the future development of melanoma gene therapy strategies.
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