Abstract

The lens epithelial derived growth factor p75 (LEDGF/p75) is a novel pro-survival and stress-inducible transcription co-activator that protects mammalian cells from various environmental stresses such as oxidative stress, heat shock, and serum starvation. This emerging cancer-related protein is highly expressed in prostate tumors and other tumor types and promotes resistance to chemotherapy in cancer cells. LEDGF/p75 is also involved in acquired immunodeficiency syndrome (AIDS) since it interacts with HIV-1 integrase to facilitate the integration and replication of the HIV virus in human cells. In addition, LEDGF/p75 has been shown to interact with MLL (mixed lineage leukemia)/menin transcription complex in leukemia cells to facilitate the transcription of cancer-associated genes and leukemic transformation. In order to understand the mechanisms by which LEDGF/p75 contributes to cancer development, we explored its interactions with other transcription factors and the influence of these interactions on its transcriptional activity. Using complementary molecular, biochemical, and cellular approaches we discovered that the amino-terminal region of LEDGF/p75 interacts with the transcription regulator and methylation associated protein MeCP2 in prostate cancer cells and other cancer cell types. We observed that both proteins regulate the expression of the heat shock protein 27 gene by transactivating its promoter region. We propose that the interaction between LEDGF/p75 and MeCP2 modulates the expression of cancer-associated genes in response to environmental stressors. These findings provide a plausible mechanism that can be targeted for the treatment of advanced prostate cancer, which is the second leading cause of cancer deaths in the United States, with a disproportional burden among African American men.

LLU Discipline

Microbiology and Molecular Genetics

Department

Basic Sciences

School

School of Medicine

First Advisor

Casiano, Carlos A.

Second Advisor

Duerksen Hughes, Penelope

Third Advisor

Linkhart, Thomas A.

Fourth Advisor

Strong, Donna D.

Fifth Advisor

Wall, Nathan R.

Degree Name

Doctor of Philosophy (PhD)

Degree Level

Ph.D.

Year Degree Awarded

January 2011

Date (Title Page)

9-1-2011

Language

English

Library of Congress/MESH Subject Headings

Prostatic Neoplasms - Microbiology; Antigens, Tumor-Associated;

Subject - Local

Lens Epithelial Derived Growth Factor p75; LEDGF/p75; Cancer-related proteins; Acquired Immunodeficiency Syndrome; AIDS; Mixed Lineage Leukemia; Prostate Cancer; African-American Males

Type

Dissertation

Page Count

203 p.

Digital Format

Application/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 & Dissertations

Collection Website

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

Repository

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

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