Year of Award

2009

Document Type

Dissertation

Degree Type

Doctor of Philosophy (PhD)

Degree Name

Toxicology

Department or School/College

Department of Biomedical and Pharmaceutical Sciences

Committee Chair

Mark A. Pershouse

Commitee Members

Elizabeth Putnam, J. Douglas Coffin, J. Stephen Lodmell, Scott Samuels

Keywords

malignant mesothelioma

Abstract

The highly aggressive cancer, malignant mesothelioma, responds poorly to available treatment options. As most individuals diagnosed with these tumors succumb to the disease within about 2 years of diagnosis, it is imperative to develop a more thorough understanding of molecular mechanisms of the disease and thus design more suitable therapeutic options. Neurofibromatosis Type 2 (NF2) is one of the most commonly inactivated tumor suppressor genes in mesothelioma. The downstream signaling pathways that may be disrupted as a result of this inactivation are not entirely understood. Conversely, the tumor suppressor gene that is often referred to as the "Genome Gatekeeper," TP53, is rarely inactivated in mesothelioma tumors. As TP53 is mutated in the majority of human cancers, in those cancers where TP53 is not mutated, its function may be regulated by other mechanisms. Evidence suggests that NF2 may be upstream in a signaling cascade of TP53, such that NF2 is responsible for MDM2 degradation. MDM2 is a negative regulator of p53 (the protein product of TP53), so that loss of NF2 would ultimately result in decreased function of p53.

The hypothesis of this study is that inactivation of NF2 plays a critical role in cellular growth dysregulation through altering normal regulation of MDM2 and thus p53 levels. To test this hypothesis, the role of the NF2 gene in regulating p53 function and cellular growth in "normal" mesothelial cells and in a mesothelioma cell culture model were assessed. Normal function of NF2 was restored by transfection of a wild-type NF2 construct in a mesothelioma cell culture model. Additionally, NF2 expression was reduced in "normal" mesothelial cells by shRNA knockdown. In both in vitro models, alterations in NF2 expression resulted in significant changes in cell cycle mechanisms, including proliferative, apoptotic, and cell cycle arrest. These events were linked to aberrant p53 function. Finally, an in vivo mouse model was used to determine the role Nf2 in the development of pleural mesothelioma following asbestos exposure. A better understanding of the molecular mechanisms that are disrupted following NF2 inactivation will help with design of more effective therapeutic strategies.

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© Copyright 2009 Amy Kay Erbe