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Examination of the Role of the Hu Proteins, Hur and Hud, in Prostate Cancer Cells

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Examination of the Role of the Hu Proteins, Hur and Hud, in Prostate Cancer Cells Examination of the Role of the Hu Proteins, HuR and HuD, in Prostate Cancer Cells. Christin Florence Down This thesis is presented for the degree of Doctor of Philosophy to the School of Medicine and Pharmacology, University of Western Australia. January 2007 i Declaration. This thesis contains published work and/or work prepared for publication, some of which has been co-authored . The bibliographic details of the works and where they appear in the thesis are set out below. (The candidate must attach to this declaration a statement detailing the percentage contribution of each author to the work. This must been signed by all authors. Where this is not possible, the statement detailing the percentage contribution of authors should be signed by the candidate’s Coordinating Supervisor). This thesis contains experimental data from the following co-authored work: Hu Proteins are Expressed and Regulate Androgen Receptor Expression and Cell Proliferation in Prostate Cancer. Christin F Down , Dianne J Beveridge, Michael R Epis, Ricky Lareu, Lisa M Stuart, Britt Granath, Dominic C Voon, Henry Furneaux, Cecily Metcalf, Jacqueline Bentel and Peter J Leedman. Submitted to Cancer Research . The relative contribution of authors is as follows: Christin Down (the Candidate): 55% Dianne J Beveridge 6 % Michael R Epis 6 % Ricky Lareu 3 % Lisa M Stuart 3 % Britt Granath 3 % Dominic Voon 3 % Henry Furneaux 3 % Cecily Metcalf 3 % Jacqueline Bentel 5 % Peter J Leedman 10 % Data from the manuscript described above are presented in this thesis in the following figures, and were performed by the investigator indicated: Figure 3.1A : Dr Cecily Metcalfe, Department of Pathology, Royal Perth Hospital. Figure 3.1C: Dr Ricky Lareu, School of Medicine and Pharmacology, University of Western Australia. Figure 3.2A : Britt Granath, School of Medicine and Pharmacology, University of Western Australia. Figures 3.2C and 3.4B : Dr Dominic Voon, School of Medicine and Pharmacology, University of Western Australia. Figure 3.3: Dianne Beveridge, School of Medicine and Pharmacology, University of Western Australia. Figure 6.10: Michael Epis, School of Medicine and Pharmacology, University of Western Australia. Professor Peter J Leedman ……………………………… Christin Down …………………………….. ii Thesis Summary . Prostate cancer is a significant cause of morbidity and mortality in the male population, and despite its high prevalence, there have been few advances in prostate cancer management during the past 20 years. The primary treatment for prostate cancer centres around inhibition of androgen signalling, halting tumour growth through down-regulation of important proliferative genes under control of the androgen receptor (AR). Frequently, prostate cancer progresses to an androgen-independent state that is resistant to AR-targeting therapies and is characterised by persistent AR expression and re-expression of AR- regulated genes. Understanding the regulation of AR in prostate cancer is therefore of paramount importance for the development of new treatments to control advanced disease. The AR is regulated post-transcriptionally at the level of mRNA stability, and a UC-rich cis -element (“ARUC”) within the 3’ untranslated region (3’UTR) of the AR mRNA has been identified, which is bound by an mRNA-stabilising protein, HuR. HuR is a member of a family of four related mRNA-binding proteins that includes HuD, which is typically expressed in neuronal tissue. In this thesis, HuD expression was examined immunohistochemically in a cohort of 12 prostate specimens and was detected at low levels in benign prostatic hyperplasia (BPH), with up-regulated expression in prostate cancers, in particular in high-grade tumours. HuD mRNA expression was also confirmed in the LNCaP prostate cancer cell line using reverse-transcription (RT)-PCR. Like HuR, HuD binds U-rich mRNA and RNA electrophoretic mobility shift assays (REMSA’s) confirmed HuD binding to the UC-rich ARUC motif in the AR mRNA 3’UTR, an association that could be disrupted by introduction of point mutations into the ARUC motif. In addition, the AR mRNA was found to co-immunoprecipitate with HuD and HuR from LNCaP cell lysates in immunoprecipitation RT-PCR (IP-RT-PCR) experiments, suggesting that both of these proteins are associated with the AR mRNA in vivo. The ubiquitously expressed HuR protein was also detected in both normal and malignant prostate tissues using immunohistochemistry, as well as in the nuclei of LNCaP and 22Rv1 prostate cancer cells. As HuR was highly iii expressed in these cell lines, effects of HuR knockdown on AR expression and activity was examined. Reduction of HuR was associated with a decrease in AR protein levels, evaluated using western blotting, however an effect on AR transcriptional activity could not be identified in androgen-responsive luciferase reporter assays. Quantitative PCR (qPCR) of actinomycin D treated cells was used to demonstrate that the half-life of the AR mRNA was significantly decreased following siRNA-mediated knockdown of HuR levels. Interestingly, reduction of HuR expression in 22Rv1 cells was also associated with a significant increase in cell proliferation. To determine mRNA targets of HuR which may be important in prostate cancer proliferation or progression, an oligonucleotide micro-array analysis was performed on 22Rv1 cells that had been treated with siRNA directed against HuR. This identified a number of growth-associated signalling pathways in which multiple genes were down-regulated, including the mitogen-activated protein kinase (MAPK), focal adhesion, vascular endothelial growth factor (VEGF) and Wingless type/MMTV integration (Wnt) signalling pathways, as well as ubiquitin-mediated proteolysis. Further qPCR and IP-RT-PCR analysis of a subset of the regulated genes that contained 3’UTR HuR consensus binding sites confirmed mRNA down-regulation following HuR siRNA treatment and in vivo interaction with HuR of the CREBBP, PCAF, ELK1 and PAK2 transcripts. In summary, results presented in this thesis have identified aberrant up- regulation of expression of the RNA-binding protein HuD in prostate cancer, which may contribute to the maintenance of AR expression via binding and stabilisation of the AR mRNA. HuR has been identified as an important protein for the control of AR gene expression and prostate cancer cell proliferation. Furthermore, HuR regulates expression of a range of key genes involved in transcription and cellular signalling, implicating it as an important potential target for therapeutics. iv Table of Contents. Declaration…………………………………………………………………………….ii Thesis Summary……………………………………………………………………..iii Table of Contents…………………………………………………………………….v Acknowlegements……………………………………………………………………x Awards Received…………………………………………………………………….xi Publications and Presentations Arising from this Thesis……………………….xii Index of Figures…………………………………………………………………….xiv Index of Tables…………. …………………………………………………………xvi Abbreviations……………………………………………………………………….xvii 1 Chapter 1: Introduction. .............................................................................2 1.1 The Prostate and Prostate Cancer. ....................................................2 1.1.1 Structure and Function of the Prostate Gland. ............................2 1.1.2 Androgen Effects on Prostate Tissue. .........................................4 1.1.3 Prostate Cancer...........................................................................5 1.1.3.1 Treatment of Prostate Cancer. .............................................6 1.2 The Androgen Receptor. ....................................................................8 1.2.1 Structure......................................................................................8 1.2.2 AR Activity. ................................................................................ 10 1.2.3 Regulation of Androgen Receptor Transcriptional Activity......... 11 1.2.4 Regulation of Androgen Receptor Protein Levels...................... 15 1.3 The Androgen Receptor in Prostate Cancer..................................... 16 1.3.1 AR Gene Mutations. .................................................................. 17 1.3.2 AR Gene Amplification. ............................................................. 18 1.3.3 AR Co-Activators in Prostate Cancer. ....................................... 18 1.3.4 Cell Line Models of Prostate Cancer. ........................................ 22 1.4 Post-transcriptional Regulation of mRNA. ........................................ 22 1.4.1 Structural and Sequence Motifs in mRNA Processing and Turnover. ................................................................................... 23 1.4.2 RNA-Binding Proteins in Post-Transcriptional Regulation. ........ 31 1.4.3 Hu/ELAV Family of RNA Binding-Proteins. ............................... 33 1.4.3.1 Hu Binding Sites................................................................. 38 1.4.3.2 Modulation of Hu Protein Activity........................................ 39 1.4.4 Shared Targets, Different Outcomes......................................... 40 v 1.4.5 Mechanisms of AURE-Mediated Decay. ................................... 43 1.5 Post-Transcriptional Regulation of the Androgen Receptor.............. 44 1.5.1 Androgen Regulation of the AR mRNA Turnover. ..................... 44 1.5.2 Structure of the AR mRNA. ....................................................... 44 1.6 Summary and Statement of Aims. .................................................... 47 1.6.1 Summary. .................................................................................
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