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Title

FXR1 Drives Oncogenic Transformation Through Regulation of Translation

Date of Award

Winter 12-15-2013

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Molecular Cell Biology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Cells use translation to respond quickly and robustly to many different situations. Eukaryotic translation is not only controlled globally but can be as specific as a single mRNA transcript allowing a massive response or fine tuning by the cell. Cancer is a complex disease with much genetic variation, but commonly deregulates translation to further drive cancer progression. While much is known about cap-dependent translation and its effect on cancer, little is known about the role of cap-independent translation and how cancer may use this process to its advantage in responding to stress and overcoming therapies.

In this dissertation, I set out to further understand the role translation plays in cancer. I first sought to investigate the mechanism of cap-independent translation in lung cancer via a high-throughput screen. The hypothesis that a hit from this screen would not only provide a much needed tool to this field but also shed light on regulators of the mechanism and possible drug target for cancer therapy. Finally, I wanted to determine what appeared to be a hot zone for cancer in the 3q26 locus.

Somatic copy number variation is a common theme in nearly all cancers. The 3q26 locus is commonly amplified in numerous human tumors and contains several known oncogenes including PIK3CA. In human breast cancers, alterations in PIK3CA and other known oncogenes on 3q26 do not predict overall survival, indicating that other novel oncogenes might be contained within the locus. Here, we reveal that the FXR1 gene on 3q26 is amplified or overexpressed in a significant number of human cancers, and its expression predicts overall survival in breast cancer patients. Targeted reduction in FXR1 expression significantly diminishes proliferation in breast cancer cells that overexpress endogenous FXR1. Moreover, overexpression of FXR1 in normal human mammary epithelial cells and immortal mouse fibroblasts results in tremendous gains in proliferation, cellular transformation and in vivo tumorigenesis positing FXR1 as a bona fide oncogene. In this context, FXR1 functions to bind RNA to promote mRNA translation and enhanced protein synthesis. FXR1 selectively induces the translation of existing H-Ras mRNAs by promoting the transition from initiation to elongation, thus providing a link between translational regulation and mitogenic signal transduction pathways controlled by Ras. These results suggest that the 3q26 locus is a master regulator of oncogenic translational control in tumor cell biology.

Language

English (en)

Chair and Committee

Jason D Weber

Committee Members

Sergej Djuranovic, Greg Longmore, Michael Tomasson, Heather True-Krob

Comments

Permanent URL: https://doi.org/10.7936/K7CR5R8T

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