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by Gaofeng Fan BS, Biology, 2003 Nanjing University, P.R. China Thesis Advisor: Céline Gélinas, PhD Graduate Program: Biochemistry and Molecular Biology CABM 010 Busch Campus Piscataway Thursday, July 30, 2009 10:00 am Abstract The Rel/NF-kappaB transcription factors are important for the immune and inflammatory response, cell proliferation, apoptosis and oncogenesis. We characterized the regulation of their transcriptional and oncogenic activities and that of its anti-apoptotic target Bfl-1 (Bcl2a1, A1) by co-regulatory proteins and by post-translational modifications. We found that peptidyl-prolyl isomerase PIN1, which is frequently upregulated in human cancers in which Rel/NF-kappaB is activated, associates with the Rel proteins, promotes their nuclear accumulation and markedly enhances transformation of primary lymphocytes. Inhibition of Pin1 function with juglone or shRNA led to cytoplasmic relocalization of c-Rel in human lymphoma cells, markedly interfered with their proliferation and suppressed Rel/NF-kappaB-dependent gene expression. This demonstrates that PIN1 is an important regulator of Rel/NF-kappaB’s transforming activity and suggests that PIN1 is a potential therapeutic target in Rel/NF-kappaB-dependent leukemia/lymphomas. Impaired cell death (apoptosis) is a major factor in tumor development and chemoresistance. Rel/NFkappaB plays an important role in this context by transactivating pro-survival genes like as the anti-apoptotic Bcl-2 family member Bfl-1. Bfl-1 is upregulated in many human tumors and is important for tumor cell survival and chemoresistance. We investigated how Bfl-1 suppresses cell death and its regulation by the ubiquitin-proteasome. We showed that Bfl-1 functions as a selective antagonist of pro-apoptotic proteins tBid and Bak. We also found that ubiquitination-resistant Bfl-1 mutants significantly predispose mice to leukemia/lymphoma and that Bfl-1 functionally cooperates with Lck in tumorigenesis. These results demonstrate that ubiquitination is key to regulate Bfl-1’s function and suggest that mutations in bfl-1 or in the signaling pathways that control its ubiquitination may predispose to cancer. Additionally, these data suggest that strategies to promote Bfl-1 ubiquitination might improve therapy of drug-resistant tumors. In this regard, we identified an important role for the PI3K-Akt-GSK3 axis in Bfl-1’s post- translational regulation. Akt inhibitors enhanced Bfl-1 ubiquitination and degradation and restored the response of Bfl-1-expressing cells to death-inducing agents. Notably, these combinations significantly enhanced apoptosis in drug-resistant human diffuse large B cell lymphoma (DLBCL) cell lines, as did knockdown of endogenous Bfl-1 with siRNA. Overall, these results identified a novel strategy to target Bfl-1 that may lead to improved treatments for Bfl-1-positive tumors. |
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