All ETDs from UAB

Advisory Committee Chair

Etty N Benveniste

Advisory Committee Members

Dale Benos

Chenbei Chang

Gerald Fuller

Burton Nabors

Lisa Schwiebert

Document Type

Dissertation

Date of Award

2009

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Glioblastoma (GBM) is an incurable tumor of the central nervous system (CNS). Over the past 50 years, little progress has made in improving the quality of life and median lifespans of patients who are diagnosed with this devastating disease. However, new insights into the aberrant signaling pathways at the root of GBM pathology are providing new targets for next generation cancer therapies. Two signaling pathways that are commonly upregulated in GBM are NF-kappaB and STAT3. Importantly, tumor models in which NF-kappaB and STAT3 signaling are inhibited have demonstrated the importance of these pathways to GBM growth and proliferation. Therefore, better understanding of the regulation of these pathways is required so that therapies can be designed against them in the future. We have found that the peptidyl prolyl isomerase Pin1 plays an important role in the regulation of both the NF-kappaB and STAT3 pathways. Through an interaction with the NF-kappaB protein p65, we found that Pin1 enhances the activation of NF-kappaB, as measured by pS276 p65. Furthermore, we found that this enhanced NF-kappaB signaling results in the differential expression of NF-kappaB-regulated genes, including the upregulation of the angiogenic factor IL-8. We also determined that the mechanism through which Pin1 enhanced IL-8 expression was by increasing the recruitment of active p65 to the IL-8 promoter. Finally, using a migration assay, we found that Pin1 enhanced the migration of cells stimulated with TNF-alpha, suggesting an NF-kappaB-mediated mechanism. We have also determined that Pin1 acts as a positive regulator of the JAK2/STAT3 pathway. Pin1 enhanced STAT3 activity in whole-cell lysates, as measured by pY705 and pS727 STAT3. Pin1 also increased the levels of total and pS727 STAT3 in the nucleus, and this led to increased recruitment of STAT3 to the promoter of an important STAT3 target, SOCS3. SOCS3 mRNA and protein expression was also increased by Pin1. Finally, using an invasion assay, we found that Pin1 decreases the invasive properties of unstimulated glioma cells. On the whole, this project has made new discoveries as to the role of Pin1 in NF-kappaB and STAT3 signaling. We hope that his work, in combination with innovations in GBM cell targeting and delivery, will eventually lead to benefits in GBM therapy.

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