Molecular mode of action of 1,25-dihydroxyvitamin D3: from chromatin to protein.

Although vitamin D can be derived from nutrition, the main supply of vitamin D3 derives from photosynthesis in the skin. Therefore, vitamin D is not considered as a true vitamin but rather as a precursor of a hormone. The biologically active form of vitamin D, 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] exerts its genomic effects through the vitamin D receptor (VDR). Upon binding of the ligand, VDR heterodimerizes with retinoid X receptor and binds to Vitamin D Response Elements in the promoter region of targets genes to induce/repress their expression. Besides its effects on bone and mineral homeostasis, 1,25-(OH)2D3 inhibits the growth and induces differentiation of a wide variety of normal and malignant cells. These effects of 1,25-(OH)2D3 open perspectives for the use of this molecule in the treatment of cancer, psoriasis and other hyperproliferative disorders however its calcemic side effects hamper its therapeutic applications. We developed successfully analogues of 1,25-(OH)2D3 with potent antiproliferative and lower calcemic effects. The aim of this project is to get a better insight in the 1,25-(OH)2D3-mediated signaling cascade by combining high-throughput Chromatin Immunoprecipitation-sequencing (ChIP-sequencin), microarray and proteomic analyses. Once the exact nature of the signaling cascades induced by 1,25(OH)2D3 is characterized, it will become possible to identify directly regulated key target genes that could be used as important markers for the activity profile of newly developed analogues.

Keywords:Proteomics, Microarray, ChlP sequencing, Analogs, Antiproliferative, Cancer, Vitamin D

Disciplines:Endocrinology and metabolic diseases