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Inactivation of the vitamin D receptor enhances susceptibility of murine skin to UV-induced tumorigenesis.

Inactivation of the vitamin D receptor enhances susceptibility of murine skin to UV-induced tumorigenesis tumorigenesis /tu·mor·i·gen·e·sis/ (-jen´e-sis) oncogenesis.

tu·mor·i·gen·e·sis
n.
Formation or production of tumors.
 

Ellison TI, Smith MK, Gilliam AC and MacDonald PN

J Invest Dermatol, 2008, 128, 2508-2517

Vitamin D can protect against a number of forms of carcinogenesis, although its role in skin cancer is only beginning to be studied. The biologically active form of vitamin D is 1, 25-dihydroxyvitamin [D.sub.3]. This hormone binds to the vitamin D receptor (VDR) and promotes association with its heterodimeric partner, the retinoid X receptor retinoid X receptor One of 2 receptors for retinoids; RXR plays a key role in organ development, in particular of the skin. Cf Retinoic acid receptor. . This complex regulates transcription by binding to specific response elements in the promoter regions of target genes. Vitamin D is primarily produced in the skin from 7-dehydrocholesterol under the influence of UV light. Conversely, of course, UVB UVB ultraviolet B; see ultraviolet.  can also promote the production of skin cancer, with approximately one million people diagnosed with non-melanoma skin cancer per year, accounting for half of all diagnosed tumours.

Knockout mice have provided important physiological insights into the vitamin D endocrine system. In fact, this has pointed to the hypothesis that VDR may be able to act independently of its ligand, vitamin D, in keratinocytes. For example there appears to be an uncoupling of the receptor-ligand interaction on hair follicle cycling. There is evidence that phosphorylation phosphorylation, chemical process in which a phosphate group is added to an organic molecule. In living cells phosphorylation is associated with respiration, which takes place in the cell's mitochondria, and photosynthesis, which takes place in the chloroplasts.  can directly activate VDR [1] or it may be possible that keratinocyte growth factor The Keratinocyte Growth Factor (KGF) is a growth factor present in the epithelialization-phase of wound healing. In this phase, keratinocytes are covering the wound, forming the epithelium.  pathways may directly activate the receptor pathway. In this work, the authors provide evidence that VDR, but not its ligand vitamin D, is required for in vivo resistance to chemically and UVB-induced skin carcinogenesis in mice. Furthermore, they go on to show that VDR is not required for UVB-induced upregulation of protein p53 and activity, since increases in p53 were detected in VDR knockout mice. However, thymine dimer repair was markedly reduced in mice lacking the VDR, indicating that these mice have defective DNA repair mechanisms in UV-induced damage. VDR was also shown to be required for the growth arrest of the cell cycle following UV exposure, with fewer apoptotic cells detected. Following repeated UV exposures over a 2-week period, wild-type keratinocytes in the epidermis became more proliferative and epidermal thickening increased to a greater level compared to VDR-deficient mice. These data suggest absence of VDR makes the mice more sensitive to skin tumorigenesis induced by chronic UV treatment since they were unable to mount an effective thickening of the epidermis as compared to the wild-type mice.

Reference

[1.] Barletta F, Freedman LP and Christakos S. Enhancement of VDR-mediated transcription by phosphorylation: correlation with increased interaction between the VDR and DRIP205, a subunit of the VDR-interacting protein coactivator complex. Mol Endocrinol, 2002, 16, 301-314.
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Author:Knaggs, H.E.
Publication:Clinical Dermatology
Date:Dec 1, 2008
Words:434
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