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.

Keywords::

• NPM–RAR
• acute promyelocytic leukemia
• TNF
• TRADD
• NFκB
• JNK

Acknowledgements

The authors would like to thank Richard Steinman, MD, PhD, Daniel Johnson, PhD and Preet Chaudhary, MD, PhD for valuable discussions and sharing of reagents. The HIV luciferase plasmid was a kind gift from Robert Ferris, MD, PhD. This work was supported by NIH R01 CA67346 and P30 CA047904. A.C. and I.A. contributed equally to the project, and should be considered co-first authors.

Potential conflict of interest

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