Date of Award

1-1-2008

Degree Name

Doctor of Philosophy

Department

Molecular, Cellular, and Systemic Physiology

First Advisor

Collard, Dr. Michael

Abstract

Deformed epidermal autoregulatory factor-1 (DEAF-1) is a mammalian transcription factor and is associated with of fetal development, human depression, and cancer. DEAF-1 knock out mice were generated using conventional gene knockout methods to study the standard null phenotype. Deaf-1 is necessary for neural tube development and 68% of Deaf-1 null mice embryos show excencephaly. Loss of Deaf-1 is associated with decreased apoptotic response in knockout mouse embryo fibroblasts. Heterozygous Deaf-1 males develop prostate inflammation and prostate T-Cell lymphomas suggesting DEAF-1 haploinsuffciency produces a genetic defect in prostate function. The Deaf-1 knockout mice also develop lung and liver tumors and these data show a potential role of Deaf-1 in the molecular basis of tumor formation. To facilitate the elucidation of the genetic events that may play an important role in the development or tumorigenesis of the prostate gland, a transgenic mouse line with prostate-specific knock out of Deaf-1 was produced. Somatic loss of Deaf-1 prostate specific knockout mice led prostate inflammation and benign changes in branching of prostate lobes. These changes did not progress to prostate tumors within one year indicating somatic loss of Deaf-1 does not perpetuate prostate carcinomas. The molecular basis of DEAF-1 function was studied in PC3 prostate cancer cell line that overexpress epitope tagged DEAF-1. DEAF-1 was upregulated following genotoxic stress like X-ray, ultraviolet radiation, and hydrogen peroxide. Increase in DEAF-1 protein levels could be due to post transcriptional mechanisms leading to protein stabilization. DEAF-1 over expression in PC3 cell lines leads to a increase in G2/M arrest suggesting altered levels of DEAF-1 in cancer may lead to disruption of growth arrest and cell cycle check points. Finally, cDNA microarray comparison of DEAF-1 overexpressing PC3 cell lines reveals increased expression of the Nicotinamide N- Methyl transferase (NNMT) gene. Thus this work shows new functions and genes regulated by DEAF-1 using knockout mouse models and prostate cancer cell lines.

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