1. ¹Department of Cancer Biology, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157, USA
2. ²The National Institute of Health, National Cancer Institute, Center for Cancer Research, Bethesda, MD 20892, USA
3. ³Department of Pharmacology, University of Colorado Health Sciences Center, Fitzsimmons Campus, PO Box 6511, Mail Stop 8303, Aurora, CO 80045, USA

Correspondence: A Thorburn, Department of Pharmacology, University of Colorado Health Sciences Center, UCHSC at Fitzsimmons, L18-6100 RC1 South Tower, PO Box 6511, Mail Stop 8303, Aurora, CO 80045-0508, USA. Tel: 303-724-3290; Fax: 303-724-3663; E-mail: Andrew.Thorburn@UCHSC.edu

Received 30 June 2004; Revised 6 December 2004; Accepted 22 December 2004; Published online 11 March 2005.

Abstract

TNFR1 associated death domain protein (TRADD) contains an N-terminal TRAF binding domain and a C-terminal death domain along with nuclear import and export sequences that cause shuttling between the cytoplasm and nucleus. The death domain of TRADD contains the nuclear import sequence and expression of the core death domain (nuclear TRADD) results in exclusive nuclear localization and activation of a distinct apoptotic pathway. Cytoplasmic TRADD activates apoptosis through Fas-associated death domain protein (FADD) and caspase-8 activation that was blocked by caspase inhibitors or dominant-negative FADD. These inhibitors did not inhibit death induced by nuclear TRADD, which could only be inhibited by combining caspase inhibitors and a serine protease inhibitor. The pathway activated by nuclear TRADD requires caspase-9 catalytic activity. However, apoptosis activating factor deficiency confers only partial protection from death. This pathway represents an alternate means by which TRADD can regulate cell death independently of FADD and caspase-8 that occurs from the nucleus rather than the cytoplasm.