Apoptosis Induction by Targeting Interferon Gamma Receptor 2 (IFNgammaR2) in Prostate Cancer: Ligand (IFNgamma)-Independent Novel Function of IFNgammaR2 as a Bax Inhibitor
Annual rept. 1 Aug 2012-31 Jul 2013
CASE WESTERN RESERVE UNIV CLEVELAND OH SCHOOL OF MEDICINE
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In our previous study, we found that IFN R2 has previously unknown function as an inhibitor of Bax. Bax is a key mediator of apoptosis. We found that IFN R2 is overexpressed in prostate cancer, and we hypothesize that abnormally high level of IFN R2 confers apoptosis resistance of prostate cancer. In this project, we will investigate the role of IFN R2 in drug resistance of prostate cancer and explore the development of therapeutic peptide that can activate Bax-induced apoptosis in prostate cancer by inactivating IFN R2. In the first 12 months Year 1, we planned to perform experiments investigating the binding domains of IFN R2 and Bax. We generated plasmids encoding mutant cDNAs of Bax and IFN R2 in which previously known functional domains are deleted. These mutant proteins were expressed in the cell, and their Bax inhibition activity and binding activities were analyzed. As a result, we found that the IFN R2 binding domain of Bax is localized to amino acids 54-198 of Bax, and Bax binding domain of IFN R2 is localized to amino acids 296-337 of IFN R2. We will perform further investigation to identify minimum essential binding domains in IFN R2 and Bax. These studies will help us to design therapeutic peptide that can disrupt Bax-IFN R2 interaction to promote Bax-induce apoptosis triggered by chemotherapy in prostate cancer.
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