Chan Chi-keung. / Thesis (M.Sc.)--Chinese University of Hong Kong, 2000. / Includes bibliographical references (leaves 93-107). / Abstracts in English and Chinese. / List of Tables --- p.ix / List of Figures --- p.x / Chapter 1. --- Literature Review --- p.1 / Chapter 1.1 --- Introduction --- p.1 / Chapter 1.2 --- Oncogenic anatomy of the prostate gland --- p.1 / Chapter 1.3 --- Characteristics of prostate cancer --- p.7 / Chapter 1.4 --- Incidences of prostate cancer --- p.8 / Chapter 1.5 --- Risk factors for prostate cancer --- p.14 / Chapter 1.5.1 --- Endogenous risk factors --- p.14 / Chapter (A) --- Age --- p.14 / Chapter (B) --- Race --- p.16 / Chapter (C) --- Family history --- p.21 / Chapter (D) --- Hormonal factors --- p.24 / Chapter (I) --- Androgen --- p.24 / Chapter (II) --- Vitamin D --- p.32 / Chapter 1.5.2 --- Exogenous risk factors --- p.41 / Chapter (A) --- Dietary factors --- p.41 / Chapter (B) --- Body Mass Index & physical condition --- p.44 / Chapter (C) --- Occupation --- p.46 / Chapter (D) --- Vasectomy --- p.47 / Chapter (E) --- Others --- p.48 / Chapter 2. --- Introduction to the project --- p.49 / Chapter 3. --- Objectives --- p.50 / Chapter 4. --- Materials and Methods --- p.51 / Chapter 4.1 --- Prostate cancer cases --- p.51 / Chapter 4.2 --- Controls --- p.52 / Chapter (A) --- Benign prostatic hyperplasia --- p.52 / Chapter (B) --- Population control --- p.52 / Chapter 4.3 --- DNA extraction --- p.53 / Chapter 4.4 --- Amplification of target DNA --- p.54 / Chapter 4.5 --- Allele typing --- p.55 / Chapter 4.6 --- Statistical analysis --- p.55 / Chapter 5. --- Results --- p.60 / Chapter 5.1 --- Optimization of DNA extraction --- p.60 / Chapter 5.2 --- Optimization of PCR condition --- p.61 / Chapter 5.3 --- Allele typing --- p.65 / Chapter 5.4 --- Characteristics of subjects samples --- p.68 / Chapter 5.4.1 --- Age of subjects and tumor grading --- p.68 / Chapter 5.4.2 --- Genotype typing --- p.69 / Chapter (A) --- Bsm genotype --- p.69 / Chapter (B) --- Fok genotype --- p.69 / Chapter 6. --- Discussions --- p.73 / Chapter 6.1 --- Technical issues --- p.73 / Chapter (A) --- DNA extraction --- p.73 / Chapter (B) --- Primer design --- p.76 / Chapter (C) --- Determination of the optimal PCR condition --- p.77 / Chapter (D) --- Restriction enzyme digestion --- p.82 / Chapter 6.2 --- Age distribution of prostate cancer patients --- p.83 / Chapter 6.3 --- Genotype frequency --- p.84 / Chapter 6.4 --- Histopathological samples of case and control --- p.87 / Chapter 6.5 --- Vitamin D receptor genotypes and prostate cancer --- p.89 / Chapter 7. --- Conclusions --- p.92 / Chapter 8. --- References --- p.93

Vitamin D is a precursor to a steroid hormone, 1,25 dihydroxyvitamin D (1,25(OH)2D). After its discovery and the characterization of its receptor, the vitamin D receptor (VDR), it was initially thought only to be involved in calcium homeostasis, but further research revealed an important role for vitamin D in the regulation of cell growth and differentiation of such cells as osteoblasts and bone marrow adipocytes. 1,25(OH)2D has also been shown to be a strong inhibitor and pro-differentiator of keratinocytes. The anti-proliferative and pro-differentiative properties of this hormone have led to studies where 1,25(OH)2D anticancer properties were assessed and initial findings that showed a requirement of other factors beyond VDR to induce 1,25(OH)2D signaling led to the identification of the retinoid X receptor, a common heterodimeric partner for several hormone receptors. The focus of thesis was to further elucidate the structure-function relationship of both the vitamin D receptor and the retinoid X receptor. Additionally, contributions to work directed towards further identifying the effects of vitamin D on osteoblast differentiation and survival. Interactions of 1,25(OH) 2D3 with its cognate receptor, identifying a key amino acid (Tryptophan 286) required for ligand contact and transcriptional activation, are described in Chapter 2. Mechanisms of vitamin D action on mesenchymal stem cell differentiation, promotion of osteoblast induction and maturation, and inhibition of adipocyte differentiation, are eluicidated in Chapter 3. Chapter 4 illustrates the effects of RAS/RAF/Mitogen-activated protein kinase mediated RXRalpha phosphorylation on the three-dimensional structure of the RXR/nuclear receptor partner heterodimers. Furthermore, this chapter reveals the inhibitory effect of the phosphorylation of a critical amino acid (serine 260) on the interaction of the AF-2 domain of the RXR with several coactivators, resulting in a decrease in the signaling potential of multiple steroid hormone receptors. The findings of this thesis further the knowledge of several areas of vitamin D biology, including both the canonical areas of bone formation, and the non-canonical area of vitamin D and cancer.

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