Journal of Cellular Biochemistry, DOI: 10.1002/jcb.25070
Angelika Dampf-Stone1,‡, Shane Batie1,2,‡, Marya Sabir1,‡, Elizabeth T. Jacobs3,4, Jamie H. Lee1, G. Kerr Whitfield2, Mark R. Haussler2 and Peter W. Jurutka1,2, pjurutka at asu.edu
1 School of Mathematical and Natural Sciences, Arizona State University, Glendale, AZ 85306
2 Department of Basic Medical Sciences, The University of Arizona, College of Medicine, Phoenix, AZ, 85004
3 University of Arizona Cancer Center, Tucson AZ, 85724
4 Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ, 85724
The 1,25-dihydroxyvitamin D3 (1,25D) hormone is derived from vitamin D generated in skin or obtained from the diet, and binds to and activates the vitamin D receptor (VDR) in target tissues including kidney, colon/small intestine, and bone/muscle.
We tested resveratrol for its ability to modulate VDR signaling, using vitamin D responsive element (VDRE) and mammalian two-hybrid (M2H) transcriptional system technology. Via VDRE-based assays in kidney, colon and myoblast cells, VDR-mediated transcription was activated by resveratrol, and a cooperative effect on transactivation was observed with resveratrol plus 1,25D. The M2H assay revealed a modest, resveratrol-induced dimerization of VDR with its retinoid X receptor (RXR) heteropartner.
Cells treated with both resveratrol and 1,25D displayed synergistic stimulation of VDR-RXR heterodimerization, while resveratrol antagonized rexinoid-mediated RXR-RXR homodimerization. Increased transactivation in response to resveratrol was also observed with a subset of other nuclear receptors and their respective cognate responsive elements.
Evaluation of wild-type versus a ligand-binding domain mutant VDR revealed that hormone-responsiveness to 1,25D was severely depressed, while the response to resveratrol was only moderately attenuated.
Moreover, radiolabeled 1,25D-displacement assays demonstrated an increase in VDR-bound 1,25D in the presence of resveratrol.
Thus, resveratrol may affect VDR and other nuclear receptors indirectly, likely via the ability of resveratrol to:
- 1) potentiate 1,25D binding to VDR,
- 2) activate RXR, and/or 3) stimulate SIRT1, an enzyme known to deacetylate nuclear receptors.
The results of this study elucidate a possible pathway for crosstalk between two nutritionally derived lipids, vitamin D and resveratrol, both of which converge on VDR signaling.
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