The Role of the Vitamin D Receptor and ERp57 in Photoprotection by 1α,25-Dihydroxyvitamin D3
| Autor: | Vivienne E. Reeve, Clare Gordon-Thomson, Peter J. Malloy, Mark S. Rybchyn, Vanessa B. Sequeira, Rebecca S. Mason, Gary M. Halliday, Anthony W. Norman, David Feldman, Wannit Tongkao-on, Ilka Nemere |
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| Rok vydání: | 2012 |
| Předmět: |
Transcriptional Activation
Calcitriol Ultraviolet Rays DNA damage Mutation Missense Protein Disulfide-Isomerases Pyrimidine dimer Biology Calcitriol receptor chemistry.chemical_compound Endocrinology medicine Vitamin D and neurology Humans Molecular Biology Cells Cultured Original Research Cell Nucleus General Medicine Fibroblasts Molecular biology Protein Structure Tertiary Up-Regulation chemistry Vitamin D3 Receptor Pyrimidine Dimers Photoprotection Receptors Calcitriol Familial Hypophosphatemic Rickets Tumor Suppressor Protein p53 Cholecalciferol Protein Binding medicine.drug |
| Zdroj: | Molecular Endocrinology. 26:574-582 |
| ISSN: | 1944-9917 0888-8809 |
| DOI: | 10.1210/me.2011-1161 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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