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PAK1 Promotes the Proliferation and Inhibits Apoptosis of Human Spermatogonial Stem Cells via PDK1/KDR/ZNF367 and ERK1/2 and AKT Pathways.
Molecular Therapy - Nucleic Acids ( IF 8.8 ) Pub Date : 2018-06-21 , DOI: 10.1016/j.omtn.2018.06.006
Hongyong Fu 1 , Wenhui Zhang 1 , Qingqing Yuan 1 , Minghui Niu 1 , Fan Zhou 1 , Qianqian Qiu 1 , Guoping Mao 1 , Hong Wang 1 , Liping Wen 1 , Min Sun 1 , Zheng Li 2 , Zuping He 3
Affiliation  

Spermatogonial stem cells (SSCs) have significant applications in reproductive and regenerative medicine. However, nothing is known about genes in mediating human SSCs. Here we have explored for the first time the function and mechanism of P21-activated kinase 1 (PAK1) in regulating the proliferation and apoptosis of the human SSC line. PAK1 level was upregulated by epidermal growth factor (EGF), but not glial cell line-derived neurotrophic factor (GDNF) or fibroblast growth factor 2 (FGF2). PAK1 promoted proliferation and DNA synthesis of the human SSC line, whereas PAK1 suppressed its apoptosis in vitro and in vivo. RNA sequencing identified that PDK1, ZNF367, and KDR levels were downregulated by PAK1 knockdown. Immunoprecipitation and Western blots demonstrated that PAK1 interacted with PDK1. PDK1 and KDR levels were decreased by ZNF367-small interfering RNAs (siRNAs). The proliferation of the human SSC line was reduced by PDK1-, KDR-, and ZNF367-siRNAs, whereas its apoptosis was enhanced by these siRNAs. The levels of phos-ERK1/2, phos-AKT, and cyclin A were decreased by PAK1-siRNAs. Tissue arrays showed that PAK1 level was low in non-obstructive azoospermia patients. Collectively, PAK1 was identified as the first molecule that controls proliferation and apoptosis of the human SSC line through PDK1/KDR/ZNF367 and the ERK1/2 and AKT pathways. This study provides data on novel gene regulation and networks underlying the fate of human SSCs, and it offers new molecular targets for human SSCs in translational medicine.



中文翻译:

PAK1通过PDK1 / KDR / ZNF367和ERK1 / 2和AKT途径促进人精原干细胞的增殖并抑制其凋亡。

精原干细胞(SSCs)在生殖和再生医学中具有重要的应用。但是,关于介导人类SSC的基因一无所知。在这里,我们首次探索了P21活化激酶1(PAK1)在调节人SSC系增殖和凋亡中的功能和机制。PAK1水平由表皮生长因子(EGF)上调,但不由胶质细胞系衍生的神经营养因子(GDNF)或成纤维细胞生长因子2(FGF2)上调。PAK1促进人类SSC系的增殖和DNA合成,而PAK1抑制其细胞凋亡在体外体内。RNA测序鉴定出PDK1,ZNF367和KDR的水平受PAK1敲低的影响而下调。免疫沉淀和Western印迹证明PAK1与PDK1相互作用。ZNF367-小干扰RNA(siRNA)降低了PDK1和KDR的水平。PDK1-,KDR-和ZNF367-siRNA减少了人SSC系的增殖,而这些siRNA增强了其凋亡。PAK1-siRNA降低了phos-ERK1 / 2,phos-AKT和细胞周期蛋白A的水平。组织阵列显示,非阻塞性​​无精子症患者的PAK1水平较低。集体地,PAK1被确定为第一个通过PDK1 / KDR / ZNF367和ERK1 / 2和AKT途径控制人SSC系增殖和凋亡的分子。这项研究提供了有关人类SSC命运的新型基因调控和网络的数据,

更新日期:2018-06-21
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