| Summary: | 碩士 === 高雄醫學大學 === 公共衛生學研究所碩士班 === 93 === Proteins can be phosphorylated at serine ,tyrosine ,threonine residues by protein kinases. Hormone dependent phosphorylation of nuclear receptor has been reported and may be involved in regulation of DNA binding, protein-protein interaction, nuclear localization and gene transactivation. Most members of the steroid hormone receptor superfamily, including progesterone receptor、glucocorticoid receptor、thyroid hormone receptor、estrogen receptor、androgen receptor and vitamin D receptor, have been shown to be phosphoprotein.
The steroid hormone 1α,25-dihydroxyvitamin D3 (vitamin D3) plays an important role in the regulation of numerous physiological and cellular processes including calcium and phosphorous homeostasis, cell growth, differentiation and apoptosis. The biological effect of vitamin D3 is mainly mediated via the vitamin D3 receptor (VDR). Binding of vitamin D3 to VDR promotes the interaction between VDR and retinoid X receptor (RXR) and enhances the formation of VDR/RXR heterodimer. The heterodimer then attaches to the vitamin D3 response element (VDRE) in the promoter of target genes to trigger or repress gene transcription.
Osteocalcin is synthesized and secreted by the osteoblast and whose concentration in serum has been increasingly used as an index of bone formation. Previous report shows that vitamin D could regulate osteocalcin by VDR-RXR complex and vitamin D receptor was a phophoprotein. In this thesis ,we use site-mutagenesis to create serine-mutated VDR constructs. Further, we define how the phosphorylation of VDR affect VDR-RXR complex or other co-factors to regulate the expression of osteocalcin. Besides, we will study the importance of AF2 domain in the transcriptional regulation of Osteocalcin gene.
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