Abstract

Despite significant clinical and basic science advancements, cancer remains a devastating disease that affects people of all ages, races, and background. Survivin, the fourth most common transcript found in cancer cells, is a protein that is thought to be involved in the enhanced proliferation, survival, and metastasis of cancer cells. Therefore understanding how this gene is regulated is potentially of vital importance to improving cancer management and therapy. Our work has identified a novel transcriptional regulator of survivin called Yin Yang 1 (YY1). YY1 is a transcription factor that has been observed to activate some gene promoters and repress others, and it is gaining increasing interest as a target of cancer therapy. Our work shows for the first time that YY1 is a repressor of survivin transcription and can do so by physically interacting with the survivin promoter. Furthermore, YY1 appears to contribute to basal survivin transcriptional activity, indicating that disruption of its binding may in part contribute to survivin overexpression after cellular stress events including chemo- and radiotherapy. It is also important to use gained mechanistic understandings of cancer initiation and progression to design logical new approaches to cancer therapy. Pancreatic cancer is one of the most deadly forms of cancer known, and survivin expression has been observed to be an important factor in pancreatic cancer aggressiveness or resistance to therapy. Therefore survivin downregulation may represent an important means of gaining improved treatment efficacy in pancreatic cancer. Using combined gemcitabine and proton radiation therapy, we show that downregulation of survivin and its family member X-linked IAP may lead improved cell death following treatment, particularly when gemcitabine therapy is instituted prior to proton radiotherapy.

LLU Discipline

Biochemistry

Department

Basic Sciences

School

School of Medicine

First Advisor

Wall, Nathan R.

Second Advisor

Duerksen-Hughes, Penelope

Third Advisor

Kirsch, Wolff

Fourth Advisor

Oberg, Kerby

Fifth Advisor

Reeves, Mark

Degree Name

Doctor of Philosophy (PhD)

Degree Level

Ph.D.

Year Degree Awarded

2014

Date (Title Page)

3-2014

Language

English

Library of Congress/MESH Subject Headings

Pancreatic Neoplasms; Carcinoma - Pancreatic Ductal; Proton Therapy; Inhibitor of Apoptosis Proteins; YY1 Transcription Factor

Subject - Local

Gemcitabine Therapy; Pancreatic Cancer; Chemotherapy; Radiotherapy; Survivin Transcription

Type

Dissertation

Page Count

119

Digital Format

PDF

Digital Publisher

Loma Linda University Libraries

Usage Rights

This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights.

Collection

Loma Linda University Electronic Theses and Dissertations

Collection Website

http://scholarsrepository.llu.edu/etd/

Repository

Loma Linda University. Del E. Webb Memorial Library. University Archives

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