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Extrinsic apoptosis is impeded by direct binding of the APL fusion protein NPM-RAR to TRADD.

ABSTRACT: A subset of acute promyelocytic leukemia (APL) cases has been characterized by the t(5;17)(q35;q21) translocation variant, which fuses nucleophosmin (NPM) to retinoic acid receptor ? (RARA). The resultant NPM-RAR fusion protein blocks myeloid differentiation and leads to a leukemic phenotype similar to that caused by the t(15;17)(q22;q21) PML-RAR fusion. The contribution of the N-terminal 117 amino acids of NPM contained within NPM-RAR has not been well studied. As a molecular chaperone, NPM interacts with a variety of proteins implicated in leukemogenesis. Therefore, a proteomic analysis was conducted to identify novel NPM-RAR-associated proteins. TNF receptor type I-associated DEATH domain protein (TRADD) was identified as a relevant binding partner for NPM-RAR. This interaction was validated by coprecipitation and colocalization analysis. Biologic assessment found that NPM-RAR expression impaired TNF-induced signaling through TRADD, blunting TNF-mediated activation of caspase-3 (CASP3) and caspase-8 (CASP8), to ultimately block apoptosis.This study identifies a novel mechanism through which NPM-RAR affects leukemogenesis.

SUBMITTER: Chattopadhyay A 

PROVIDER: S-EPMC4163521 | biostudies-other | 2014 Sep

REPOSITORIES: biostudies-other

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Extrinsic apoptosis is impeded by direct binding of the APL fusion protein NPM-RAR to TRADD.

Chattopadhyay Anuja A   Hood Brian L BL   Conrads Thomas P TP   Redner Robert L RL  

Molecular cancer research : MCR 20140717 9

<h4>Unlabelled</h4>A subset of acute promyelocytic leukemia (APL) cases has been characterized by the t(5;17)(q35;q21) translocation variant, which fuses nucleophosmin (NPM) to retinoic acid receptor α (RARA). The resultant NPM-RAR fusion protein blocks myeloid differentiation and leads to a leukemic phenotype similar to that caused by the t(15;17)(q22;q21) PML-RAR fusion. The contribution of the N-terminal 117 amino acids of NPM contained within NPM-RAR has not been well studied. As a molecular  ...[more]