Extrinsic apoptosis is impeded by direct binding of the APL fusion protein NPM-RAR to TRADD.
Extrinsic apoptosis is impeded by direct binding of the APL fusion protein NPM-RAR to TRADD.
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DOI：
10.1158/1541-7786.mcr-14-0080
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发表时间：
2014-09
期刊：
影响因子：
--
通讯作者：
Redner RL
中科院分区：
文献类型：
--
作者：
Chattopadhyay A;Hood BL;Conrads TP;Redner RL
急性早幼粒细胞白血病（APL）病例的一个子集的特征是t（5;17）（q35;q21）易位变异体，该变异体将核磷蛋白（NPM）融合到视黄酸受体α（RARA）。所得到的NPM-RAR融合蛋白阻断骨髓分化，并导致类似于由t（15;17）（q22;q21）PML-RAR融合引起的白血病表型。NPM-RAR中所含NPM的N-末端117个氨基酸的贡献尚未得到充分研究。作为一种分子伴侣，NPM与多种与白血病发生有关的蛋白质相互作用。因此，进行蛋白质组学分析以鉴定新的NPM-RAR相关蛋白。肿瘤坏死因子受体1型相关的死亡结构域蛋白（TRADD）被确定为NPM-RAR的相关结合伴侣。通过共沉淀和共定位分析验证了这种相互作用。生物学评估发现，NPM-RAR表达通过TRADD损害TNF诱导的信号传导，减弱TNF介导的半胱天冬酶3（CASP 3）和半胱天冬酶8（CASP 8）的活化，最终阻断细胞凋亡。这项研究确定了NPM-RAR影响白血病发生的一种新机制。
A subset of acute promyelocytic leukemia (APL) cases have been characterized by the t(5;17)(q35;q21) translocation variant which fuses nucleophosmin (NPM) to retinoic acid receptor alpha (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. Tumor necrosis factor receptor type 1-associated DEATH domain protein (TRADD) was identified as a relevant binding partner for NPM-RAR. This interaction was validated by co-precipitation and co-localization analysis. Biological 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 impacts leukemogenesis.