PAK1 Promotes the Proliferation and Inhibits Apoptosis of Human Spermatogonial Stem Cells via PDK1/KDR/ZNF367 and ERK1/2 and AKT Pathways

Fu, Han; Zhang, Wenhui; Yuan, Quan; Niu, Minghui; Zhou, Fan; Qiu, Qianqian; Mao, Guoping; Wang, Hong; Wen, Lei; Sun, Min; Li, Zheng; He, Zuping

doi:10.1016/j.omtn.2018.06.006

Cited by 42 publications

(35 citation statements)

References 48 publications

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“…Wang et al found that overexpression of PAK1 promoted cell proliferation in cutaneous T-cell lymphoma via suppression of PUMA and p21 [34]. Fu et al found that PAK1 promoted the proliferation and inhibited apoptosis of human spermatogonial stem cells via PDK1/KDR/ZNF367 and ERK1/2 and AKT pathways [30]. However, in the present study, we found that up-regulation of PAK1 by IL-1β inhibited proliferation of chondrocytes.…”

Section: Discussioncontrasting

confidence: 81%

“…PAK1 is widely distributed in the human body, which has been shown to interact with nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in multiple cell types [10]. Previous studies showed that PAK1 was involved in the regulation of NADPH oxidase in diseases associated with inflammatory activation, proliferation and angiogenesis of endothelial cells [29,30]. In addition, PAK1 was also confirmed to control mitogen-activated protein kinase (MAPK), such as c-Jun N-terminal kinase (JNK) and p38 MAP kinases, and NF-κB activity [26].…”

Section: Discussionmentioning

confidence: 99%

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Up-regulation of P21-activated kinase 1 in osteoarthritis chondrocytes is responsible for osteoarthritic cartilage destruction

Wang²,

Wang³

et al. 2020

Bioscience Reports

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Osteoarthritis is mainly caused by a degenerative joint disorder, which is characterized by the gradual degradation of articular cartilage and synovial inflammation. The chondrocyte, the unique resident cell type of articular cartilage, is crucial for the development of osteoarthritis. Previous studies revealed that P21-activated kinase-1 (PAK1) was responsible for the initiation of inflammation. The purpose of the present study was to determine the potential role of PAK1 in osteoarthritis. The level of PAK1 expression was measured by Western blot and quantitative real-time PCR in articular cartilage from osteoarthritis model rats and patients with osteoarthritis. In addition, the functional role of aberrant PAK1 expression was detected in the chondrocytes. We found that the expression of PAK1 was significantly increased in chondrocytes treated with osteoarthritis-related factors. Increased expression of PAK1 was also observed in knee articular cartilage samples from patients with osteoarthritis and osteoarthritis model rats. PAK1 was found to inhibit chondrocytes proliferation and to promote the production of inflammatory cytokines in cartilages chondrocytes. Furthermore, we found that PAK1 modulated the production of extracellular matrix and cartilage degrading enzymes in chondrocytes. Results of the present studies demonstrated that PAK1 might play an important role in the pathogenesis of osteoarthritis.

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Section: Discussioncontrasting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Up-regulation of P21-activated kinase 1 in osteoarthritis chondrocytes is responsible for osteoarthritic cartilage destruction

Wang²,

Wang³

et al. 2020

Bioscience Reports

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“…Interestingly, Pak1 promotes the proliferation and inhibits apoptosis via the Akt pathway. 35) Similarly, silencing of Pak1 significantly decreased the phosphorylation of Akt and deactivated Akt signaling pathway. Given that miR-665 inhibitor could significantly depress the accumulation of ROS and cell apoptosis by promoting the phosphorylation of Akt, silencing of Pak1 could inhibit the protection of miR-665 inhibitor and depress the phosphorylation of Akt in H/Rtreated H9c2 cells.…”

Section: Discussionmentioning

confidence: 95%

Knockdown of miR-665 Protects Against Cardiomyocyte Ischemia/Reperfusion Injury-Induced ROS Accumulation and Apoptosis Through the Activation of Pak1/Akt Signaling in Myocardial Infarction

et al. 2020

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Myocardial infarction (MI) is one of the major causes of death worldwide, and the therapeutic strategies of MI are still limited. In this study, we investigated the function of miR-665 in MI. In the present study, an ischemia/reperfusion (I/R) rat model and a hypoxia/reoxygenation (H/R)-induced H9c2 cell model were successfully established to mimic the MI for in vivo and in vitro studies. The concentrations of lactate dehydrogenase (LDH), creatine kinase-MB (CK-MB), tumor necrosis factor alpha (TNF-α), IL-6, and reactive oxygen species (ROS) were then measured. Moreover, cell viability and apoptosis were detected by MTT assay, TdT-mediated dUTP nick end labeling (TUNEL), and PI/FITC-annexin V assay. The binding of miR-665 and Pak1 was determined by luciferase assay. miR-665 was upregulated in I/R rats, and the overexpression of miR-665 significantly increased LDH, CK-MB, TNF-α, IL-6, and ROS concentrations and induced cell apoptosis, while knockdown of miR-665 had opposite results. Consistent with in vivo results, miR-665 induced cell apoptosis and ROS generation in H/R-treated H9c2 cells. More importantly, Pak1 was the target gene of miR-665, and knockdown of miR-665 depressed the accumulation of ROS and cell apoptosis by targeting Pak1 and promoting the phosphorylation of Akt, whereas knockdown of Pak1 could attenuate the protection of miR-665 inhibitor in H/ R-treated H9c2 cells. Therefore, knockdown of miR-665 protects against cardiomyocyte ischemia/reperfusion injury-induced ROS accumulation and apoptosis through activating Pak1/Akt signaling in MI. In general, understanding the biology and modulation of miR-665 may have the potential to counteract the development of MI.

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“…To identify the targets of PAK1, miRNA microarrays were performed to compare the global miRNA-expression patterns between PAK1 knockdown and the control siRNA. We utilized three pairs of small interfering RNAs (siRNAs) targeting different regions of PAK1 mRNA, and we found that the interfering effect of PAK1-siRNA2 is the most prominent 24 . Total RNA was extracted from human SSCs at 24 hr after PAK1-siRNA2 and control siRNA treatment.…”

Section: Resultsmentioning

confidence: 99%

“…To our knowledge, very little is known about the role of genetic and epigenetic factors in controlling human spermatogenesis and male infertility. We have recently demonstrated that PAK1 is regulated by epidermal growth factor (EGF) and that PAK1 promotes the proliferation and decreases apoptosis of human SSCs through PDK1-KDR-ZNF367 and ERK1/2-AKT 24 . Notably, low levels of PAK1 may be associated with NOA patients 24 .…”

Section: Discussionmentioning

confidence: 99%

miRNA-31-5p Mediates the Proliferation and Apoptosis of Human Spermatogonial Stem Cells via Targeting JAZF1 and Cyclin A2

Zhou

Yuan

et al. 2019

Molecular Therapy - Nucleic Acids

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Several lines of evidence highlight the important application of human spermatogonial stem cells (SSCs) in translational medicine. The fate decisions of SSCs are mainly mediated by genetic and epigenetic factors. We have recently demonstrated that PAK1 regulates the proliferation, DNA synthesis, and early apoptosis of human SSCs through the PDK1/KDR/ZNF367 and ERK1/2 and AKT pathway. However, the underlying epigenetic mechanism of PAK1 in human SSCs remains unknown. In this study, we found that the level of miRNA-31-5p was elevated by PAK1 knockdown. CCK-8, PCNA, and 5-ethynyl-2′-deoxyuridine (EDU) assays revealed that miRNA-31-5p mimics inhibited cell proliferation and DNA synthesis of human SSCs. Annexin V/propidium iodide (PI) staining and flow cytometry showed that miRNA-31-5p increased the early and late apoptosis of human SSCs. Furthermore, JAZF1 was predicted and verified as a target of miRNA-31-5p, and the three-dimensional (3D) structure model of JAZF1 protein was illustrated. JAZF1 silencing led to a reduction of cell proliferation and DNA synthesis as well as an enhancement of the early and late apoptosis of human SSCs. Finally, miRNA-31-5p mimics decreased the level of cyclin A2 rather than cyclin D1 or cyclin E1, and JAZF1 knockdown led to the reduction of cyclin A2 in human SSCs. Collectively, miRNA-31-5p regulates the proliferation, DNA synthesis, and apoptosis of human SSCs by the PAK1-JAZF1-cyclin A2 pathway. This study thus offers a novel insight into the molecular mechanisms underlying the fate determinations of human SSCs and might provide novel targets for molecular therapy of male infertility.

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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

Cited by 42 publications

References 48 publications

Up-regulation of P21-activated kinase 1 in osteoarthritis chondrocytes is responsible for osteoarthritic cartilage destruction

Up-regulation of P21-activated kinase 1 in osteoarthritis chondrocytes is responsible for osteoarthritic cartilage destruction

Knockdown of miR-665 Protects Against Cardiomyocyte Ischemia/Reperfusion Injury-Induced ROS Accumulation and Apoptosis Through the Activation of Pak1/Akt Signaling in Myocardial Infarction

miRNA-31-5p Mediates the Proliferation and Apoptosis of Human Spermatogonial Stem Cells via Targeting JAZF1 and Cyclin A2

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