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The role of the vitamin D receptor and ERp57 in photoprotection by 1α,25-dihydroxyvitamin D3.
- Source :
-
Molecular endocrinology (Baltimore, Md.) [Mol Endocrinol] 2012 Apr; Vol. 26 (4), pp. 574-82. Date of Electronic Publication: 2012 Feb 09. - Publication Year :
- 2012
-
Abstract
- UV radiation (UVR) is essential for formation of vitamin D(3), which can be hydroxylated locally in the skin to 1α,25-dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)]. Recent studies implicate 1,25-(OH)(2)D(3) in reduction of UVR-induced DNA damage, particularly thymine dimers. There is evidence that photoprotection occurs through the steroid nongenomic pathway for 1,25-(OH)(2)D(3) action. In the current study, we tested the involvement of the classical vitamin D receptor (VDR) and the endoplasmic reticulum stress protein 57 (ERp57), in the mechanisms of photoprotection. The protective effects of 1,25-(OH)(2)D(3) against thymine dimers were abolished in fibroblasts from patients with hereditary vitamin D-resistant rickets that expressed no VDR protein, indicating that the VDR is essential for photoprotection. Photoprotection remained in hereditary vitamin D-resistant rickets fibroblasts expressing a VDR with a defective DNA-binding domain or a mutation in helix H1 of the classical ligand-binding domain, both defects resulting in a failure to mediate genomic responses, implicating nongenomic responses for photoprotection. Ab099, a neutralizing antibody to ERp57, and ERp57 small interfering RNA completely blocked protection against thymine dimers in normal fibroblasts. Co-IP studies showed that the VDR and ERp57 interact in nonnuclear extracts of fibroblasts. 1,25-(OH)(2)D(3) up-regulated expression of the tumor suppressor p53 in normal fibroblasts. This up-regulation of p53, however, was observed in all mutant fibroblasts, including those with no VDR, and with Ab099; therefore, VDR and ERp57 are not essential for p53 regulation. The data implicate the VDR and ERp57 as critical components for actions of 1,25-(OH)(2)D(3) against DNA damage, but the VDR does not require normal DNA binding or classical ligand binding to mediate photoprotection.
- Subjects :
- Cell Nucleus metabolism
Cells, Cultured
Familial Hypophosphatemic Rickets pathology
Fibroblasts radiation effects
Humans
Mutation, Missense
Protein Binding
Protein Disulfide-Isomerases genetics
Protein Disulfide-Isomerases metabolism
Protein Structure, Tertiary
Pyrimidine Dimers metabolism
Receptors, Calcitriol genetics
Receptors, Calcitriol metabolism
Transcriptional Activation
Tumor Suppressor Protein p53 genetics
Tumor Suppressor Protein p53 metabolism
Ultraviolet Rays
Up-Regulation
Calcitriol physiology
Fibroblasts metabolism
Protein Disulfide-Isomerases physiology
Receptors, Calcitriol physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1944-9917
- Volume :
- 26
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Molecular endocrinology (Baltimore, Md.)
- Publication Type :
- Academic Journal
- Accession number :
- 22322599
- Full Text :
- https://doi.org/10.1210/me.2011-1161