NPM-RAR binding to TRADD selectively inhibits caspase activation, while allowing activation of NF kappa B and JNK

作者：Chattopadhyay Anuja; Abecassis Irina; Redner Robert L^*

来源：Leukemia and Lymphoma, 2015, 56(12): 3401-3406.

DOI：10.3109/10428194.2015.1023799

• NPM-RAR
• acute promyelocytic leukemia
• TNF
• TRADD
• NF kappa B
• JNK

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 B (NF kappa B) 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 NF kappa B and JNK. We propose that inhibition of TNF activation of apoptosis, while preserving TNF activation of NF kappa B and JNK pathways that stimulate cell growth and survival, represents a novel mechanism through which NPM-RAR contributes to development of the leukemic phenotype.

• 出版日期2015-12-2