Regulation of Leukemic Cell Differentiation through the Vitamin D Receptor at the Levels of Intracellular Signal Transduction, Gene Transcription, and Protein Trafficking and Stability
1α,25-Dihydroxyvitamin D3 (1,25(OH)2D) exerts its biological activities through vitamin D receptor (VDR), which is a member of the superfamily of steroid receptors, that act as ligand-dependent transcription factors. Ligated VDR in complex with retinoid X receptor (RXR) binds to regulatory regions of 1,25(OH)2D-target genes. 1,25(OH)2D is able to induce differentiation of leukemic blasts towards macrophage-like cells. Many different acute myeloid leukemia (AML) cell lines respond to 1,25(OH)2D by increasing CD14 cell surface receptor, some additionally upregulate CD11b and CD11c integrins. In untreated AML cells VDR protein is present in cytosol at a very low level, even though its mRNA is continuously expressed. Ligation of VDR causes protein stabilization and translocation to the cell nuclei, where it regulates transcription of target genes. Several important groups of genes are regulated by 1,25(OH)2D in HL60 cells. These genes include differentiation-related genes involved in macrophage function, as well as a gene regulating degradation of 1,25(OH)2D, namely CYP24A1. We summarize here the data which demonstrate that though some cellular responses to 1,25(OH)2D in AML cells are transcription-dependent, there are many others which depend on intracellular signal transduction, protein trafficking and stabilization. The final effect of 1,25(OH)2D action in leukemic cells requires all these acting together. 1. Introduction The primary role of 1α,25-dihydroxyvitamin D3 (1,25(OH)2D) is to maintain calcium and phosphate homeostasis in vertebrate organisms via actions in the intestine, bones, kidneys, and parathyroid glands. However, it is well known that physiological roles of 1,25(OH)2D reach much beyond calcium and phosphate homeostasis. For example, 1,25(OH)2D induces differentiation and inhibits proliferation of various normal and cancer cells, including osteoclasts, keratinocytes, and monocytes. In 1981 the group of Suda observed that 1,25(OH)2D was able to induce differentiation in the M1 murine myeloid cell line [1] and that it extended the survival of mice inoculated with leukemia cells [2]. Since then many research projects have been performed in order to prepare ground for clinical use of 1,25(OH)2D or of its low calcemic analogs in leukemia treatment [3–5]. There are two major signal transduction pathways activated by 1,25(OH)2D in target cells. The most important and the best documented is the so-called “genomic pathway,” with its most important player a vitamin D receptor (VDR). The less well described is “nongenomic pathway,” which consists of
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