Hematopoietic Substrate-1-Associated Protein X-1 Regulates the Proliferation and Apoptosis of Endothelial Progenitor Cells Through Akt Pathway Modulation
Hematopoietic Substrate-1-Associated Protein X-1 Regulates the Proliferation and Apoptosis of Endothelial Progenitor Cells Through Akt Pathway Modulation
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DOI：
10.1002/stem.2741
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发表时间：
2018-03-01
期刊：
影响因子：
5.2
通讯作者：
Wei, Ying
中科院分区：
文献类型：
--
作者：
Guo, Xin-Bin;Deng, Xin;Wei, Ying
内皮前体细胞（endothelial precursor cells，EPCs）参与多种生理和病理过程的血管发生。EPCs的增殖和存活机制有待于进一步研究，以开发有效的胶质瘤治疗方法。造血基质-1相关蛋白X-1（HAX-1）是一种抗凋亡蛋白，在多种恶性肿瘤中发挥重要作用。然而，HAX-1对EPCs的作用及其机制尚不清楚。本研究旨在观察HAX-1对EPCs增殖和凋亡的影响，并探讨其作用机制。根据我们的结果，HAX-1在EPCs中过表达。克隆形成和5-乙炔基-2-脱氧尿苷增殖实验结果表明，HAX-1促进EPCs增殖。流式细胞仪检测显示HAX-1基因敲除后细胞周期主要阻滞于G 0/G1期。凋亡分析显示HAX-1对氧化应激诱导的EPCs凋亡具有保护作用。Western blot结果显示HAX-1可抑制caspase级联反应的激活，降低p21、Bcl-2相关X蛋白和p53的表达。HAX-1还通过促进蛋白MDM-2和Akt 1的磷酸化来增强p53的降解速率和泛素化。免疫共沉淀和免疫荧光共定位试验进行测试HAX-1的Akt 1和热休克蛋白90（Hsp 90），这是至关重要的Akt 1的活性之间的相互作用的影响。结论：HAX-1可通过Hsp 90促进Akt 1通路，降低p53表达水平，促进EPCs增殖，抑制其凋亡。
Endothelial precursor cells (EPCs) are involved in vasculogenesis of various physiological and pathological processes. The proliferation and survival mechanism of EPCs needs to be explored further for the purpose of developing an effective glioma treatment. Hematopoietic substrate-1-associated protein X-1 (HAX-1) has been reported as an anti-apoptotic protein that plays an important role in several malignant tumors. However, the effect and mechanism of HAX-1 on EPCs remains unknown. This study aims to investigate the effect of HAX-1 on the proliferation and apoptosis of EPCs and explore its mechanism. According to our results, HAX-1 was overexpressed in EPCs. The results of clone formation and 5-ethynyl-2-deoxyuridine proliferation assay showed that HAX-1 promoted multiplication of EPCs. Flow cytometry showed HAX-1 knockout cell cycle arrest mainly in G0/G1 phase. Apoptosis analysis showed that HAX-1 could protect EPCs from apoptosis in oxidative stress. Western blot assay indicated that HAX-1 could inhibit the activation of caspase cascade and reduce the expression of p21, Bcl-2-associated X protein, and p53. HAX-1 also enhanced the degradation rate and ubiquitination of p53 through the promotion of phosphorylation of proteins MDM-2 and Akt1. Co-immunoprecipitation and immunofluorescent colocalization assays were performed to test the influence of HAX-1 on the interaction between Akt1 and heat shock protein 90 (Hsp90), which is crucial for the activity of Akt1. In conclusion, this novel study suggests that HAX-1 could facilitate the Akt1 pathway through Hsp90, which led to a decline in the levels of p53, and finally promoted the proliferation and inhibited the apoptosis of EPCs.