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首页> 外文期刊>Molecular cancer research: MCR >Extrinsic Apoptosis Is Impeded by Direct Binding of the APL Fusion Protein NPM-RAR to TRADD
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Extrinsic Apoptosis Is Impeded by Direct Binding of the APL Fusion Protein NPM-RAR to TRADD

机译：外源性凋亡受到APL融合蛋白NPM-RAR与TRADD直接结合的阻碍

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摘要

A subset of acute promyelocytic leukemia (APL) cases has been characterized by the t(15;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. 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.
机译：t（15; 17）（q35; q21）易位变体已表征了一部分急性早幼粒细胞白血病（APL）病例，该变体将核磷酸蛋白（NPM）与视黄酸受体α（RARA）融合。所得的NPM-RAR融合蛋白阻断了髓样分化，并导致类似于t（15; 17）（q22; q21）PML-RAR融合引起的白血病表型。 NPM-RAR中NPM的N端117个氨基酸的贡献尚未得到很好的研究。作为分子伴侣，NPM与多种与白血病发生有关的蛋白质相互作用。因此，进行了蛋白质组学分析，以鉴定新型的NPM-RAR相关蛋白。 I型TNF受体相关的DEATH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破坏TNF诱导的信号传导，使TNF介导的caspase-3（CASP3）和caspase-8（CASP8）活化减弱，最终阻止细胞凋亡。

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