Molecular mechanisms of Nkx3.1 gene expression in prostate epithelia : a dissertation /
| Main Author: | |
|---|---|
| Format: | Thesis Book |
| Language: | English |
| Published: |
College Station, Tex. :
Texas A&M University System Health Science Center,
2008.
|
| Subjects: |
| Abstract: | ABSTRACT: Nkx3.1 is a homeobox gene of the Nk family implicated in prostate organogenesis and carcinogenesis. Its androgen-dependent expression is accelerated after puberty with the function to fully mature and maintain the prostate gland. Nkx3.1 is the earliest prostate differentiation factor, which frequently undergoes loss heterozygosity during prostate cancer progression leading to a reduction and eventual loss in its expression. As such, our interest is to increase our understanding of how Nkx3.1 was exerted through two androgen receptor (AR) binding elements tht are located within the single intron of this two exon gene. We also identified a prostate selective region 2.7kb upstream of the Nkx3.1 transcription initiation site, which works in concert with the two intronic AR binding elements. Secondly, we examined the role of GATA factors in AR-dependent gene regulation; GATA factors also prticipate in differentiation and carcinogenesis in many organ systems. Here, we showed that the major GATA factors detected in prostate epithelial cells were GATA-2 and -3, and they participate in induction of Nkx3.1 gene expression, suggesting their roles in epithelial differentiation in prostate. Thirdly, we investigated the relationship between P13K signaling pathway and Nkx3.1. Others demonstrated that the expression of Nkx3.1 was increased in correlation with PTEN, an inhibitor of P13K pathway. In addition, AR and GATA are downstream effectors of P13K pathway. In this report, we have characterized that P13K has a positive effect on epitheliel cell identity by inducing Nkx3.1 expression in assocation with androgen. Finally, we analyzed the promoter activity of E-cadherin. Others have demonstrated that PTEN and E-cadherin, both tumor suppressors, have a mutual stabilization effect in renal epithelial cells. In this study, we demonstrated that E-cadherin promoter was significantly more active in E-cadherin-positive LNCaP cells compared to E-cadherin-negative PC-3 cells. Transcripts of potential E-cadherin repressors, Twist and Snail, were increased in prostate cancer cells. In conclusion, our study strongly suggested that a feedback loop is operational in Nkx3.1 gene regulation involving E-cadherin and P13K pathway. |
|---|---|
| Item Description: | Vita. "Major Subject: Medical Sciences". "Submitted to the Office of Research and Graduate Studies of The Texas A&M University System Health Science Center in partial fulfillment for the requirements for the degree of Doctor of Philosophy August 2008." Approved as to style and content by: Warren E. Zimmer, Farida Sohrabji, Alan Parrish, Emily Wilson, Harris J. Granger. |
| Physical Description: | xii, 123 leaves : illustrations ; 28 cm. |
| Bibliography: | Includes bibliographical references (leaves 105-123). |