title: NPM-RAR binding to TRADD selectively inhibits caspase activation, while allowing activation of NFκB and JNK.
abstract: The t(5;17) variant of acute promeylocytic leukemia (APL) expresses a fusion of nucleophosmin (NPM) with the retinoic acid receptor alpha (RARA). We have previously shown that NPM-RAR is a binding partner of the tumor necrosis factor (TNF) receptor type-I-associated DEATH domain protein, TRADD. Binding of TNF to its receptor, TNF-R, induces recruitment of TRADD, and subsequent recruitment of a cascade of proteins that ultimate activate caspase 3, nuclear factor κB (NFκB) and c-Jun N-terminal kinase (JNK). We have previously shown that NPM-RAR interaction with TRADD blocks TNF activation of caspase 3, caspase 8, poly(ADP-ribose) polymerase (PARP) cleavage and, ultimately, apoptosis. We now report that NPM-RAR expression is permissive for TNF activation of NFκB and JNK. We propose that inhibition of TNF activation of apoptosis, while preserving TNF activation of NFκB and JNK pathways that stimulate cell growth and survival, represents a novel mechanism through which NPM-RAR contributes to development of the leukemic phenotype.
authors: Department of Medicine and University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh PA 15213 USA.
authors: Anuja
authors: A
authors: Chattopadhyay
authors: Department of Medicine and University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh PA 15213 USA.
authors: Irina
authors: I
authors: Abecassis
authors: Department of Medicine and University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh PA 15213 USA.
authors: Robert L
authors: RL
authors: Redner
mesh_terms: D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D053199:TNF Receptor-Associated Death Domain Protein / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D016328:NF-kappa B; C120276:NPM-RARalpha protein, human; D015514:Oncogene Proteins, Fusion; D053199:TNF Receptor-Associated Death Domain Protein; D014409:Tumor Necrosis Factor-alpha; D048031:JNK Mitogen-Activated Protein Kinases; D020169:Caspases
keywords: JNK; NFκB; NPM–RAR; TNF; TRADD; acute promyelocytic leukemia