Molecular Mechanisms of Androgen Action : Characterization of the Androgen Regulated Gene KLK4 and the Role of Nuclear Dynamics in Androgen Receptor-Mediated Transcription
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AbstractAndrogens are important for the normal development of the male sexual characteristics, but are also involved in pathological conditions such as prostate cancer. The biological effects of androgens are mediated by the androgen receptor (AR), which is a transcription factor that regulates the expression of a wide range of target genes. In this thesis, KLK4 was identified as an androgen regulated gene that is specific to the prostate for expression. Surprisingly, KLK4 has a different gene structure than the other closely related members of the kallikrein family, resulting in an intracellular protein. Analysis of KLK4 expression in prostate tissue specimens showed that KLK4 was overexpressed in malignant prostate as compared to normal prostate glands. Experiments in prostate cancer cells furthermore demonstrated that KLK4 is a proliferative factor, possibly through the alteration of cell cycle regulatory gene expression. These data suggest that KLK4 plays an important role in prostate cancer, thus having potential utility as a diagnostic marker or therapeutic target in prostate cancer therapy. Using advanced fluorescence microcopy techniques, the interaction between AR and its target genomic sites in living cell were also studied. In contrast to the traditional view, the interaction was found to be both transient and highly dynamic, and depended on the nature of ligand. Importantly, there were intramolecular interactions between the N- and C-termini of promoter-bound AR in its active state which were important for transcriptional activity. Finally, increased AR transcriptional activity, induced by histone deacetylase inhibitors, resulted in reduced mobility of AR at its target promoter. These data support the more recent view of transcription factor–chromatin interactions as a highly dynamic system in continuous change, thus providing a kinetic and mechanistic basis for regulation of gene expression by androgens and anti-androgens in living cells.
List of papers
|Paper I. Z. Xi, T.I. Klokk, K. Korkmaz, P. Kurys, C. Elbi, B. Risberg, H. Danielsen, M. Loda, and F. Saatcioglu (2004). Kallikrein 4 is a predominantly nuclear protein and is overexpressed in prostate cancer. Cancer Research, 64 (7): 2365-70.|
|Paper II. T.I. Klokk, P. Kurys, C. Elbi, A.K. Nagaich, A. Hendarwanto, T. Slagsvold, C-Y. Chang, G.L. Hager, and F. Saatcioglu (2007). Ligand-specific dynamics of the androgen receptor at its response element in living cells. Mol Cell Biol., 27 (5): 1823-43.|
|Paper III. T.I. Klokk, A. Kilander, Z. Xi, H. Wæhre, B. Risberg, H. Danielsen, and F. Saatcioglu (2007). Kallikrein 4 is a proliferative factor that is overexpressed in prostate cancer. Cancer Research, in press.|
|Paper IV. T.I. Klokk, P. Kurys, and F. Saatcioglu (2007). Reduced mobility of the androgen receptor at its target sites in living cells in response to HDAC inhibition. Manuscript.|