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 receptor type-I –associated DEATH domain protein TRADD. Binding of TNF to its receptor, TNFR1, induces recruitment of TRADD, and subsequent recruitment of a cascade of proteins that ultimate activate caspase 3, NFκB , and JNK. We have previously shown that NPM-RAR interaction with TRADD blocks TNF activation of caspase 3, caspase 8, 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.

Current views on the genetic landscape and management of variant acute promyelocytic leukemia

“…In variant APL, NPM1-RARA bind to RARE as homodimers or as heterodimers with RXR, then recruited the co-repressor and exhibited one dominate negative effect on RARA to promote the leukemogenesis of variant APL, which was quite similar to PML-RARA [ 50 ]. In addition, NPM1-RARA could bind to TRADD to inhibit caspase activation and activate NF-κB as well as JNK signaling pathway [ 51 , 52 ], while NPM1-RARA could decrease the TP53 expression and then impaired its transcriptional activity [ 53 ]. Similar to PML-RARA, NPM1-RARA generated one ATRA-sensitive variant APL [ 42 , 44 ].…”

The one thousand and one chaperones of the NF-κB pathway

“…The translocation t(5;17)(q35;q21), occurring in acute promyelocytic leukemia, generates the aberrant protein NPM-RAR, a fusion of NPM with the retinoic acid receptor  (RAR). It has been shown that NPM-RAR binds to TRADD and inhibits caspase activation, while preserving NF-κB and JNK signaling [114]. The translocation t(2;5)(p23;q35) associated with anaplastic large cell lymphoma generates a fusion protein from NPM and anaplastic lymphoma kinase (NPM-ALK).…”

<p>Retinoic acid receptor &alpha; facilitates human colorectal cancer progression via Akt and MMP2 signaling</p>

“…AM580 causes a significant inhibition on the growth of endometrial cancer and breast tumor,13,14 that indicates RARα as a target in the therapeutic intervention of cancer. Research points out at a crucial involvement of RARα in several cancers including CRC, breast cancer, leukemia, as well as, gastric cancer via several pathways such as ERα, p38α MAPK, G protein alpha Q, Glycogen synthase kinase 3, beta/beta-catenin, nuclear factor kappa B and c-Jun N-terminal kinase 15–17. RARα is highly expressed in CRC tissues,18 however, the possibility of metastasis to be modulated by RARα to affect the progression of CRC is yet not established.…”