scholarly journals Nonstructural 3 Protein of Hepatitis C Virus Modulates the Tribbles Homolog 3/Akt Signaling Pathway for Persistent Viral Infection

2016 ◽  
Vol 90 (16) ◽  
pp. 7231-7247 ◽  
Author(s):  
Si C. Tran ◽  
Tu M. Pham ◽  
Lam N. Nguyen ◽  
Eun-Mee Park ◽  
Yun-Sook Lim ◽  
...  
Keyword(s):  
Hepatitis C ◽  
Viral Infection ◽  
Er Stress ◽  
Signaling Pathway ◽  
Akt Signaling ◽  
Hcv Rna ◽  
Akt Signaling Pathway ◽  
Protein Levels ◽  
Persistent Viral Infection ◽  
Infected Cells

ABSTRACTHepatitis C virus (HCV) infection often causes chronic hepatitis, liver cirrhosis, and ultimately hepatocellular carcinoma. However, the mechanisms underlying HCV-induced liver pathogenesis are still not fully understood. By transcriptome sequencing (RNA-Seq) analysis, we recently identified host genes that were significantly differentially expressed in cell culture-grown HCV (HCVcc)-infected cells. Of these, tribbles homolog 3 (TRIB3) was selected for further characterization. TRIB3 was initially identified as a binding partner of protein kinase B (also known as Akt). TRIB3 blocks the phosphorylation of Akt and induces apoptosis under endoplasmic reticulum (ER) stress conditions. HCV has been shown to enhance Akt phosphorylation for its own propagation. In the present study, we demonstrated that both mRNA and protein levels of TRIB3 were increased in the context of HCV replication. We further showed that promoter activity of TRIB3 was increased by HCV-induced ER stress. Silencing of TRIB3 resulted in increased RNA and protein levels of HCV, whereas overexpression of TRIB3 decreased HCV replication. By employing an HCV pseudoparticle entry assay, we further showed that TRIB3 was a negative host factor involved in HCV entry. Bothin vitrobinding and immunoprecipitation assays demonstrated that HCV NS3 specifically interacted with TRIB3. Consequently, the association of TRIB3 and Akt was disrupted by HCV NS3, and thus, TRIB3-Akt signaling was impaired in HCV-infected cells. Moreover, HCV modulated TRIB3 to promote extracellular signal-regulated kinase (ERK) phosphorylation, activator protein 1 (AP-1) activity, and cell migration. Collectively, these data indicate that HCV exploits the TRIB3-Akt signaling pathway to promote persistent viral infection and may contribute to HCV-mediated pathogenesis.IMPORTANCETRIB3 is a pseudokinase protein that acts as an adaptor in signaling pathways for important cellular processes. So far, the functional involvement of TRIB3 in virus-infected cells has not yet been demonstrated. We showed that both mRNA and protein expression levels of TRIB3 were increased in the context of HCV RNA replication. Gene silencing of TRIB3 increased HCV RNA and protein levels, and thus, overexpression of TRIB3 decreased HCV replication. TRIB3 is known to promote apoptosis by negatively regulating the Akt signaling pathway under ER stress conditions. Most importantly, we demonstrated that the TRIB3-Akt signaling pathway was disrupted by NS3 in HCV-infected cells. These data provide evidence that HCV modulates the TRIB3-Akt signaling pathway to establish persistent viral infection.

scholarly journals Anacardic acid induces cell apoptosis of prostatic cancer through autophagy by ER stress/DAPK3/Akt signaling pathway

2017 ◽  
Vol 38 (3) ◽  
pp. 1373-1382 ◽  
Author(s):  
Jing Tan ◽  
Xianzhen Jiang ◽  
Guangming Yin ◽  
Leye He ◽  
Jianye Liu ◽  
...  
Keyword(s):  
Er Stress ◽  
Signaling Pathway ◽  
Cell Apoptosis ◽  
Prostatic Cancer ◽  
Akt Signaling ◽  
Anacardic Acid ◽  
Akt Signaling Pathway

scholarly journals Highjacking of PI3K/AKT signaling pathway by Hepatitis C virus in TLR9-activated human plasmacytoid dendritic cells

Retrovirology ◽  
2010 ◽  
Vol 7 (Suppl 1) ◽  
pp. P7 ◽  
Author(s):  
Jonathan Florentin ◽  
Clélia Dental ◽  
Guylène Firaguay ◽  
Françoise Gondois-Rey ◽  
Vassili Soumelis ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Signaling Pathway ◽  
Akt Signaling ◽  
Plasmacytoid Dendritic Cells ◽  
Akt Signaling Pathway

scholarly journals NEDD4L Protein Catalyzes Ubiquitination of PIK3CA Protein and Regulates PI3K-AKT Signaling

2016 ◽  
Vol 291 (33) ◽  
pp. 17467-17477 ◽  
Author(s):  
Zixi Wang ◽  
Tingting Dang ◽  
Tingting Liu ◽  
She Chen ◽  
Lin Li ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Cancer Progression ◽  
Turnover Rate ◽  
Akt Signaling ◽  
Catalytic Subunit ◽  
Regulatory Subunit ◽  
Akt Signaling Pathway ◽  
Dynamic Regulation ◽  
Akt Activation ◽  
Protein Levels

Oncogenic PIK3CA (p110α), the catalytic subunit of class IA PI3K, plays a major role in PI3K-related cancer progression. The mechanisms underlying the dynamic regulation of PIK3CA protein levels remain unknown. Here we demonstrated that PIK3CA is regulated by polyubiquitination. We identified NEDD4L as the E3 ligase that catalyzes PIK3CA polyubiquitination, leading to its proteasome-dependent degradation. NEDD4L ubiquitinates both the free and regulatory subunit-bound PIK3CA but does not ubiquitinate the regulatory subunit of PI3K. Overexpression of NEDD4L accelerates the turnover rate of PIK3CA, whereas suppression of NEDD4L results in not only the accumulation of PIK3CA but also a paradoxical decrease of AKT activation. Thus, we propose that NEDD4L negatively regulates PIK3CA protein levels via ubiquitination and is required for the maintenance of PI3K-AKT signaling pathway.

scholarly journals Influences of S100A8 and S100A9 on Proliferation of Nasopharyngeal Carcinoma Cells through PI3K/Akt Signaling Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-7
Author(s):  
Liting Wen ◽  
Yu Ding ◽  
Xiaodong Chen ◽  
Keyong Tian ◽  
Danfeng Li ◽  
...  
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Signaling Pathway ◽  
Akt Signaling ◽  
Carcinoma Cells ◽  
Akt Pathway ◽  
Control Group ◽  
Akt Signaling Pathway ◽  
Protein Levels ◽  
Positive Rate ◽  
Sirna Group

Objective. To investigate the effects of S100A8 and S100A9 on proliferation in nasopharyngeal carcinoma cells and the regulatory effects of PI3K/Akt signaling pathway. Methods. Nasopharyngeal carcinoma cells (CNE1) were cultured and randomly divided into three groups: control group, S100A8/S100A9 overexpression group, and siRNA S100A8/S100A9 group. CCK-8 method was used to detect the effect of S100A8 and S100A9 on the viability of nasopharyngeal carcinoma cells. The effects of S100A8 and S100A9 on the colony forming ability of nasopharyngeal carcinoma cells were detected by colony forming assay. The effects of S100A8 and S100A9 on the proliferation of nasopharyngeal carcinoma cells were detected by EdU staining. The mRNA levels of PI3K and Akt were detected by RT-PCR. The expression levels of PI3K and Akt in NPC cells were detected by Western blot. Wortmannin, an inhibitor of PI3K/Akt pathway, was used to inhibit the activation of PI3K/Akt pathway. Results. Compared with the control group, the cell viability, the number of plate clones, the positive rate of EdU staining, and the mRNA and protein levels of PI3K and Akt were increased in the overexpression group. Compared with the control group, the cell viability, the number of plate clones, the positive rate of EdU staining, and the mRNA and protein levels of PI3K and Akt were decreased in the siRNA group. After inhibiting the activation of PI3K/Akt pathway, the viability of NPC cells in the overexpression group decreased significantly at 48 h and 72 h, while that in the siRNA group increased significantly. Conclusion. SiRNA S100A8 and S100A9 could inhibit the proliferation of nasopharyngeal carcinoma cells, and the underlying mechanism may be related to the inhibition of PI3K/Akt signaling pathway.

scholarly journals Gelsolin regulates proliferation, apoptosis and invasion in NK/T-cell lymphoma cells through the PI3K/Akt signaling pathway

2017 ◽  
Author(s):  
Yanwei Guo ◽  
Hongqiao Zhang ◽  
Xin Xing ◽  
Lijuan Wang ◽  
Jian Zhang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
Signaling Pathway ◽  
Cell Lymphoma ◽  
Akt Signaling ◽  
T Cell Lymphoma ◽  
Akt Signaling Pathway ◽  
Natural Killer T Cell ◽  
Protein Levels ◽  
Proliferation And Invasion

AbstractThe expression of gelsolin (GSN) is abnormal in many cancers, including extranodal nasal-type natural killer/T-cell lymphoma (NKTCL). However, the biological function of GSN and its mechanism in NKTCL remain unclear. We found GSN overexpression significantly suppressed cell proliferation, colony formationand invasion and promoted apoptosis of YTS cells. Moreover, the upregulation of GSN significantly decreased the protein levels of PI3K and p-AKT. Interestingly, blocking the PI3K/AKT signaling pathway significantly inhibited cell proliferation and invasion and promoted apoptosis of YTS cells. In conclusion, our findings indicate that GSN can suppress cell proliferation and invasion and promote apoptosis of YTS cells, which is likely to be mediated at least partially through inhibition of the PI3K/AKT signaling pathway.

scholarly journals sMEK1 promotes crosstalk between IRE1 and Akt signaling pathway: Evidence for a novel IRE1/sMEK1/Akt complex

2021 ◽  
Author(s):  
ozaira qadri ◽  
Samirul Bashir ◽  
Mariam Banday ◽  
Nazia Hilal ◽  
Khalid M Fazili
Keyword(s):  
Protein Kinase ◽  
Er Stress ◽  
Signaling Pathway ◽  
Molecular Mechanism ◽  
Ternary Complex ◽  
Akt Signaling ◽  
Akt Signaling Pathway ◽  
Unfolded Protein ◽  
Central Molecule ◽  
Protein Response

ER is facilitated with a dynamic cellular pathway namely Unfolded Protein Response (UPR): an adaptive signalling mechanism that maintains proteostasis in response to ER stress. IRE1 is one of the three transmembrane sensors of UPR with dual protein kinase and ribonuclease activities. IRE1 acts as a central molecule of UPR, which associates with a number of proteins that either regulate its activity or connect it to other pathways. Here, we report sMEK1 and Akt as novel interacting partners of IRE1 which associate to orchestrate the IRE1 and Akt signalling networks. Our study revealed that ER stress negatively regulates Akt through IRE1 protein. We found that IRE1/sMEK1/Akt form a ternary complex, which results in the dephosphorylation of Akt by protein phosphotase sMEK1 in presence of activated IRE1. Together, this study highlights the UPR/Akt link by delineating the molecular mechanism along with giving insights into the overall impact of this interaction.

scholarly journals Effect of microRNA-135a on Cell Proliferation, Migration, Invasion, Apoptosis and Tumor Angiogenesis Through the IGF-1/PI3K/Akt Signaling Pathway in Non-Small Cell Lung Cancer

2017 ◽  
Vol 42 (4) ◽  
pp. 1431-1446 ◽  
Author(s):  
Yufei Zhou ◽  
Shaoxia Li ◽  
Jiangtao Li ◽  
Dongfeng Wang ◽  
Quanxing Li
Keyword(s):  
Cell Proliferation ◽  
Signaling Pathway ◽  
Tumor Angiogenesis ◽  
Cell Apoptosis ◽  
Akt Signaling ◽  
Migration And Invasion ◽  
Akt Signaling Pathway ◽  
Expression Levels ◽  
Protein Levels ◽  
Normal Tissues

Objective: This study explored the ability of microRNA-135a (miR-135a) to influence cell proliferation, migration, invasion, apoptosis and tumor angiogenesis through the IGF-1/PI3K/Akt signaling pathway in non-small cell lung cancer (NSCLC). Methods: NSCLC tissues and adjacent normal tissues were collected from 138 NSCLC patients. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression levels of miR-135a and IGF-1, PI3K, Akt, VEGF, bFGF and IL-8 mRNA; western blotting was used to determine the expression levels of IGF-1, PI3K and Akt protein; and enzyme-linked immunosorbent assay (ELISA) was used to analyze the expression levels of VEGF, bFGF and IL-8 protein. Human NSCLC cell lines (A549, H460, and H1299) and the human bronchial epithelial cell line (HBE) were selected. A549 cells were assigned to blank, negative control (NC), miR-135a mimics, miR-135a inhibitors, IGF-1 siRNA and miR-135a inhibitors + IGF-1 siRNA groups. The following were performed: an MTT assay to assess cell proliferation, a scratch test to detect cell migration, a Transwell assay to measure cell invasion, and a flow cytometry to analyze cell apoptosis. Results: The expression level of miR-135a was lower while those of IGF-1, PI3K and Akt mRNA were higher in NSCLC tissues than in the adjacent normal tissues. Dual-luciferase reporter assay indicated IGF-1 as a target of miR-135a. The in vitro results showed that compared with the blank group, cell proliferation, migration and invasion were suppressed, mRNA and protein levels of IGF-1, PI3K, Akt, VEGF, bFGF and IL-8 were reduced, and cell apoptosis was enhanced in the miR-135a mimics and IGF-1 siRNA groups. Compared with the IGF-1 siRNA group, cells in the miR-135a inhibitors + IGF-1 siRNA group demonstrated increased cell proliferation, migration and invasion, elevated mRNA and protein levels of IGF-1, PI3K, Akt, VEGF, bFGF and IL-8 and reduced cell apoptosis. Conclusion: These findings indicated that miR-135a promotes cell apoptosis and inhibits cell proliferation, migration, invasion and tumor angiogenesis by targeting IGF-1 gene through the IGF-1/PI3K/Akt signaling pathway in NSCLC.

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