The Role of the Vitamin D Receptor and ERp57 in Photoprotection by 1α,25-Dihydroxyvitamin D3

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.

Role of VDR in 1α,25-dihydroxyvitamin D3-dependent non-genomic activation of MAPKs, Src and Akt in skeletal muscle cells

“…Evidences of VDR participation in the non-genomic action of 1,25D have been reported in the last year [34][35][36], in agreement with data from earlier studies supporting this concept. The presence of VDR in caveolae enriched plasma membrane of different tissues and cell lines was previously reported [37].…”

CYP11A1 in skin: An alternative route to photoprotection by vitamin D compounds

“…It should be noted that most of our studies have been carried out in Skh:hr1 (hairless) mice, as this allows us to avoid artefacts associated with shaving. Although these mice have a mutation in hairless, a protein which binds to the VDR [31,32], we have reported similar effectiveness of 1,25D to reduce UVR-induced DNA damage in human keratinocytes and fibroblasts [33,34] and in people [29] as well as in various strains of mice [35]. We have also noted similar protection against UVR-induced reductions in contact hypersensitivity responses with 1,25D, in several other strains of mice, including female C57/ Bl6, BALB/C (in this test model at least) and C3h/HeN [35].…”

A synthetic lethal screen identifies the Vitamin D receptor as a novel gemcitabine sensitizer in pancreatic cancer cells

“…49 Moreover, topically applied VD3 protected skin from UV induced photodamage. 50 We first compared the sensitization achieved with VDR knockdown to that of Chk1 knockdown, a well known chemosensitization target that overrides the DNA damage checkpoint and promotes mitotic catastrophe. [51][52][53][54][55][56] We conducted clonogenic assays as this was more sensitive and reliable than the short term viability assays.…”