Novel Insights into p63 Expression and Function in Prostate
UNIFORMED SERVICES UNIV OF THE HEALTH SCIENCES BETHESDA MD F EDWARD HEBERT SCHOOL OF MEDICINE
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The central hypothesis of this dissertation is that p53 homologues exist and that identification of these genes will provide a better understanding of the role p53 gene family plays in biology and cancer. At the beginning of this research, no p53 related gene was known. Subsequently, p63, a p53 homolog was described by other investigators. p63 is necessary in the development of epithelial structures. One of the isoforms of p63, DNp63, is highly expressed in prostates, which led to the hypothesis that DNp63 has critical functions in the prostate. The studies reported here provide new insights into the expression and function of p63 in the prostate and prostate cancer. Initially, p53 homologs were sought in human prostate epithelial derived cell cultures through degenerate RT-PCR and other techniques. When the discovery of p63 using a similar approach was reported, our effort focused on p63 evaluation in tissue microarrays of benign and malignant prostate tissues. The basal cell specific expression of DNp63 in normal prostate is very striking. DNp63 is absent in other cell types in normal prostate and is not expressed in prostate adenocarcinoma. Detectable p63 was found in immortalized and early passage cell cultures derived from benign and malignant prostate tissue, but not in senescent cultures. Experimental models using adenovirus p63 expression vectors and prostate cell culture models have been developed. Evaluation of i proteins involved in cell growth and development regulation suggested that p63 overexpression reduced serine 9 phosphorylation of GSK3946 and AKT. The selective presence of DNp63 in basal cells of the prostate revealed it to be an excellent new bio-marker of prostate basal cells and epithelial cell cultures. DNp63 has already found translational utility in the diagnostic pathology setting for excluding prostate cancer in biopsies dues to its basal cell restricted expression in only benign glands.
- Medicine and Medical Research