Caspase-8 links the vitamin D receptor to death receptor-mediated apoptosis and liver toxicity

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SUN 338-365-Metabolic & Stress Receptors in Energy Homeostasis
Basic/Translational
Sunday, June 16, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SUN-354
Kai Wing Anfernee Tse*1, Panida Lungchukiet2, Ravi Kasiappan3, Jinfu Tang4, Yuefeng Sun3, Vladimir Uversky3, Bin Xue3, Santo V Nicosia5, Xiaohong Mary Zhang2 and Wenlong Bai6
1University of South Florida, Tampa, FL, 2USF College of Medicine, Tampa, FL, 3USF College of Medicine, 4USF College of Med, Tampa, FL, 5Univ of S Fl Coll of Med, Tampa, FL, 6Univ of S Florida Coll of Med, Tampa, FL
The vitamin D receptor (VDR) is a member of the steroid/thyroid nuclear hormone receptor superfamily of transcription factors that mediates the biological effects of 1α,25-dihydroxyvitamin D3 whereas death receptors are surface proteins that trigger extrinsic apoptosis in response to activation by cognate ligands such as TNF-related apoptosis-inducing ligand (TRAIL) and Fas ligand (FasL). The present study defines a novel function for the VDR in death receptor signaling by showing that it stimulates the proteolytic activity of caspase-8 (Casp8) through the binding to Casp8 dimer and the promotion of the dimer formation. The VDR-Casp8 complex occurs with endogenous proteins in human cancer cells and of mouse liver tissues and is inducible upon death receptor activation. Computer modeling and mutational analyses suggest that the complex formation involves the helix-12 in the ligand binding domain (LBD) of the VDR and the putative nuclear receptor boxes (NR boxes) present in Casp8. Through the complex, the VDR stimulates death receptor-mediated apoptosis in human cancer cells and liver cell death in mice. These findings bring together a nuclear hormone receptor and death receptors to their closest proximity known to exist to date and potentially have broad impacts on the understanding of vitamin D biology and the pathogenesis of many human diseases that involve both types of receptors and their cognate ligands.

Nothing to Disclose: KWAT, PL, RK, JT, YS, VU, BX, SVN, XMZ, WB

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: The work was supported by NIH R01 grants CA111334 and CA93666, an idea grant from US Department of Defense BC085205 and a program development grant from Ovarian Cancer research Fund.