TY - JOUR
T1 - Extrinsic apoptosis is impeded by direct binding of the APL fusion protein NPM-RAR to TRADD
AU - Chattopadhyay, Anuja
AU - Hood, Brian L.
AU - Conrads, Thomas P.
AU - Redner, Robert L.
N1 - Publisher Copyright:
© 2014 American Association for Cancer Research.
PY - 2014/9/1
Y1 - 2014/9/1
N2 - 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-RARfusion 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.TNFreceptor type I-associatedDEATHdomain 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.
AB - 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-RARfusion 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.TNFreceptor type I-associatedDEATHdomain 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.
UR - http://www.scopus.com/inward/record.url?scp=84907271521&partnerID=8YFLogxK
U2 - 10.1158/1541-7786.MCR-14-0080
DO - 10.1158/1541-7786.MCR-14-0080
M3 - Article
C2 - 25033841
AN - SCOPUS:84907271521
SN - 1541-7786
VL - 12
SP - 1283
EP - 1291
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 9
ER -