The vitamin D receptor (VDR) is known to be a phosphoprotein and inspection of the deduced amino acid sequence of human VDR (hVDR) reveals the conservation of three potential sites of phosphorylation by protein kinase C (PKC}-namely, . Immunoprecipitated extracts derived from a rat osteoblast-like osteosarcoma cell line that contains the VDR in high copy number were incubated with the et, (, and y isozymes of PKC, and VDR proved to be an effective substrate for PKC-,B, in vitro. When hVDR cDNAs containing single, double, and triple mutations of Ser-51, Ser-119, and Ser-125 were expressed in CV-1 monkey kidney cells, immunoprecipitated and phosphorylated by PKC-fi, in vitro, the mutation of Ser-51 selectively abolished phosphorylation. Furthermore, when transfected CV-1 cells were treated with phorbol 12-myristate 13-acetate, a PKC activator, phosphorylation of wild-type hVDR was enhanced, whereas that of the Ser-51 mutant hVDR was unaffected. Therefore, Ser-51 is the site of hVDR phosphorylation by PKC, both in vitro and in vivo. To evaluate the functional role of Ser-51 and its potential phosphorylation, hVDR-mediated transcription was tested using cotransfection with expression plasmids and a reporter gene that contained a vitamin D response element. Mutation of Ser-51 markedly inhibited transcriptional activation by the vitamin D hormone, suggesting that phosphorylation of Ser-51 by PKC could play a signficant role in vitamin D-dependent transcriptional activation. Therefore, the present results link the PKC signal transduction pathway of growth regulation and tumor promotion to the phosphorylation and function of VDR.The vitamin D receptor (VDR) is classified as a member of the steroid/thyroid hormone receptor superfamily of proteins by virtue of amino acid homologies within two separate domains (1-5). The N-terminal domain is configured into two zinccoordinated fingers responsible for DNA recognition and binding, whereas the C-terminal domain binds the 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] hormone. By analogy to the other members of the steroid/thyroid hormone receptor superfamily, 1,25(OH)2D3 acts by binding to the VDR, whereupon this activated hormone-receptor complex associates with recently identified response elements (6, 7) to alter transcription ofgenes such as osteocalcin. The molecular mechanism of this transcriptional alteration, especially the role of posttranslational modifications, is currently a topic of considerable interest.Several members of the steroid/thyroid hormone receptor superfamily are known to be phosphorylated, including the progesterone receptor (8), the glucocorticoid receptor (9), the thyroid hormone receptor (10), the estrogen receptor (11), and the VDR (3, 12, 13). However, the functional significance of steroid hormone receptor phosphorylation is unclear. Studies utilizing the mouse (3) and chicken (13) VDR have demonstrated that the phosphorylation ofthis receptor, in vivo, is a rapid event that is enhanced in the presence of 1,25(0H)2D3. Phosphoamino acid analysis...
The bioactive sphingolipids including, ceramide, sphingosine, and sphingosine-1-phosphate (S1P) have important roles in several types of signaling and regulation of many cellular processes including cell proliferation, apoptosis, senescence, angiogenesis, and transformation. Recent accumulating evidence suggests that ceramide- and S1P-mediated pathways have been implicated in cancer development, progression, and chemotherapy. Ceramide mediates numerous cell-stress responses, such as induction of apoptosis and cell senescence, whereas S1P plays pivotal roles in cell survival, migration, and inflammation. These sphingolipids with opposing roles can be interconverted within cells, suggesting that the balance between them is related to cell fate. Importantly, these sphingolipids are metabolically related through actions of enzymes including ceramidases, ceramide synthases, sphingosine kinases, and S1P phosphatases thereby forming a network of metabolically interrelated bioactive lipid mediators whose importance in normal cellular function and diseases is gaining appreciation. In this review, we summarize involvement of sphingolipids and their related enzymes in pathogenesis and therapy of cancer and discuss future directions of sphingolipid field in cancer research.
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