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TRIB3 destabilizes tumor suppressor PPARα expression through ubiquitin-mediated proteasome degradation in acute myeloid leukemia
Life Sciences ( IF 6.1 ) Pub Date : 2020-07-01 , DOI: 10.1016/j.lfs.2020.118021
Xu Luo 1 , Liang Zhong 2 , Lihua Yu 3 , Ling Xiong 4 , Wenran Dan 4 , Jian Li 2 , Jiao Ye 2 , Xuan Chu 4 , Chen Liu 2 , Beizhong Liu 1
Affiliation  

Tribbles homolog 3 (TRIB3) is emerging as a multifunctional oncoprotein associated with various cellular events in different tumors. However, the regulatory mechanism of TRIB3 in acute myeloid leukemia (AML) remains unknown. This study aims to investigate the molecular mechanisms and uncover the functions of TRIB3 in AML. Western blotting and quantitative real-time PCR were used to analyze the expression levels of TRIB3, peroxisome proliferator-activated receptor α (PPARα), apoptosis markers and autophagy markers in AML cells. Flow cytometry was used to assess cell apoptosis. The interaction of TRIB3 and PPARα was evaluated by immunofluorescence, coimmunoprecipitation, and ubiquitination assays. We demonstrated that downregulating TRIB3 in leukemic cells effectively induced apoptosis and autophagy by regulating the degradation of PPARα. Mechanistically, TRIB3 interacted with PPARα and contributed to its destabilization by promoting its ubiquitination. When PPARα was activated by its specific agonist clofibrate, the apoptosis and autophagy of AML cells were significantly enhanced. These results were confirmed by rescue experiments. Blocking PPARα expression using the PPARα inhibitor GW6471 reversed the functional influence of TRIB3 on AML cells. The aim of this study is to provide evidence of the degradation of PPARα by TRIB3 via ubiquitin-dependent proteasomal degradation. This process meditates the progression of AML and prolongs the survival of leukemic cells. As a result, these data indicate that TRIB3 is a novel and promising therapeutic target for AML treatment.

中文翻译:

TRIB3 通过泛素介导的蛋白酶体降解破坏急性髓系白血病中肿瘤抑制因子 PPARα 的表达

Tribbles 同源物 3 (TRIB3) 是一种多功能癌蛋白,与不同肿瘤中的各种细胞事件相关。然而,TRIB3在急性髓系白血病(AML)中的调节机制仍不清楚。本研究旨在研究TRIB3在AML中的分子机制并揭示其功能。采用Western blotting和实时定量PCR分析AML细胞中TRIB3、过氧化物酶体增殖物激活受体α(PPARα)、凋亡标志物和自噬标志物的表达水平。使用流式细胞术评估细胞凋亡。通过免疫荧光、免疫共沉淀和泛素化测定评估 TRIB3 和 PPARα 的相互作用。我们证明下调白血病细胞中的 TRIB3 可通过调节 PPARα 的降解有效诱导细胞凋亡和自噬。从机制上讲,TRIB3 与 PPARα 相互作用,并通过促进其泛素化而导致其不稳定。当PPARα被其特异性激动剂安妥贝特激活时,AML细胞的凋亡和自噬显着增强。这些结果得到了救援实验的证实。使用 PPARα 抑制剂 GW6471 阻断 PPARα 表达可逆转 TRIB3 对 AML 细胞的功能影响。本研究的目的是提供 TRIB3 通过泛素依赖性蛋白酶体降解来降解 PPARα 的证据。这一过程可调节 AML 的进展并延长白血病细胞的存活时间。因此,这些数据表明 TRIB3 是 AML 治疗的一个新颖且有前途的治疗靶点。
更新日期:2020-07-01
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