Document Type
Dissertation
Date of Degree
2013
Degree Name
PhD (Doctor of Philosophy)
Degree In
Molecular and Cellular Biology
First Advisor
Charles Brenner
First Committee Member
Dawn E Quelle
Second Committee Member
Michael Henry
Third Committee Member
Frederick E Domann
Fourth Committee Member
Aloysius Klingelhutz
Abstract
The FHIT gene is located on the most fragile site in the human genome. FHIT gene deletions are among the earliest and most frequent events in carcinogenesis, particularly in carcinogen-exposed tissue. Previous work in mouse and cell culture models established FHIT to be an authentic tumor suppressor. Re-expression of FHIT in cell culture causes cell death via initiation of apoptosis, but the precise mechanism underlying this process is unclear. It is well established that cellular transition from normal to transformed occurs in multiple steps and requires the accumulation of several genetic changes. Relying on the compelling phenotype of tumor development in FHIT knockout mice, this project aimed to elucidate a mechanism through which FHIT-deficient cells are primed to survive multiple genetic and environmental stresses, and promote progression of cancer. My work indicates that FHIT expression is required for the normal cellular response to oxidative stress, and presents evidence that in the absence of FHIT, an oxidative stress response pathway is superinduced. When FHIT is depleted from cells exposed to cigarette smoke, the expression of a subset of oxidative stress response genes is enhanced. Enhanced activation of these genes can occur as an adapative response to stress induced by reactive oxygen species production, and is frequently detected in cancer. Investigation into the mechanism underlying the enhanced gene expression determined that FHIT loss is associated with decreased levels of the transcriptional repressor Bach1. In this manner, we propose that loss of Fhit supports an antioxidant program that is pivotal in establishing and maintaining carcinogenic transformation.
Keywords
Bach1, Bronchial Epithelial Cells, Cigarette Smoke, Fhit, Hmox1, Oxidative Stress
Pages
xiii, 153 pages
Bibliography
Includes bibliographical references (pages 132-153).
Copyright
Copyright 2013 Jennifer Anne Boylston
Comments
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