The MAPK MEK1/2-ERK1/2 Pathway and Its Implication in Hepatocyte Cell Cycle Control

Guégan, Jean-Philippe; Frémin, Christophe; Baffet, Georges

doi:10.1155/2012/328372

Cited by 51 publications

(41 citation statements)

References 152 publications

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“…Indeed, in our study, expression levels of multiple DNA polymerases were downregulated in the eIF5B-KN cells, resulting in the accumulation of nucleotides. Our results also show that eIF5B-KN cells have prolonged S-phase of cell cycle, consistent with previous studies that have shown the involvement of the MAPK pathway in cell cycle regulation [33–34]. …”

Section: Discussionsupporting

confidence: 93%

Proteomic Analysis of eIF5B Silencing-Modulated Proteostasis

Jiang

Feng

et al. 2016

PLoS ONE

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Protein translational machinery is an important component of the proteostasis network that maintains cellular proteostasis and regulates aging and other cellular processes. Ample evidence indicates that inhibition of translation initiation factor activities enhances stress resistance in model organisms. Eukaryotic translation initiation factor 5B (eIF5B) acts by joining the pre-40S subunit with the 60S ribosomal unit to form an 80S-like complex during protein translational initiation. Reduced eIF5B expression may disrupt proteostasis and trigger cellular processes associated with stress responses. In this study, the physiological effects of altered eIF5B expression were examined in 293T and HepG2 cells. Cells with eIF5B-knockdown (eIF5B-KN) grew more slowly than control cells, and had a lower level of intracellular reactive oxygen species (ROS), increased resistance to oxidative stress and enhanced autophagy. Proteomic analysis showed that eIF5B knockdown resulted in upregulation of 88 proteins and downregulation of 130 proteins compared with control cells. The differentially expressed proteins were associated with diverse cellular processes including amino acid metabolism, RNA processing and protein metabolism, and DNA synthesis. Autonomous downregulation of the mitogen-activated protein kinase (MAPK) signaling pathway was identified as confirmed by western blotting and qPCR. We proposed that deactivation of MAPK pathway modulated proteostasis and induced prolonged S-phase of the cell-cycle, contributing to the slow growth of eIF5B-KN cells. eIF5B silencing also inactivated the mTOR pathway, downregulated glutamine transporters, enhanced autophagy, and decreased 28S rRNA and 5.8S rRNA expression levels which were reversed by restoration of eIF5B expression. Taken together, these results suggest that eIF5B silencing provides a negative feedback to deactivate MAPK signaling, leading to reduced cell growth. These findings provide a useful resource to further biological exploration of the functions of protein synthesis in regulation of proteostasis and stress responses.

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Section: Discussionsupporting

confidence: 93%

Proteomic Analysis of eIF5B Silencing-Modulated Proteostasis

Jiang

Feng

et al. 2016

PLoS ONE

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“…This activation seems to be related to the mammalian sterile-20-like kinase 4, which functions as an enhancer of cell proliferation and invasion through its ability to promote the process of epithelial-mesenchymal transition [32] . ERK2 may play a more prominent role in the proliferation of hepatocytes, while ERK1 may play a pro-apoptotic role [33] . An HCC type having a progenitor cell phenotype may present mechanisms of escaping the pro-apoptotic action of ERK1, which are presumably related to the mutation of p53.…”

Section: Discussionmentioning

confidence: 99%

Immunohistochemistry panel segregates molecular types of hepatocellular carcinoma in Brazilian autopsy cases

Felipe-Silva¹,

Wakamatsu²,

Cirqueira³

et al. 2016

WJG

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AIM:To assess the distribution of proteins coded by genes reported as relevant for the molecular classification of hepatocellular carcinoma (HCC). METHODS:In this retrospective cross-sectional study, the following clinicopathological data were analyzed in 80 autopsied HCC patients: sex, age, ethnicity, alcohol intake, infection with hepatitis B and/or C virus, infection with human immunodeficiency virus, prior treatment, basic and immediate causes of death, liver weight, presence of cirrhosis, number and size of nodules, gross pattern, histological grade and variants, architectural pattern, invasion of large veins, and presence and location of extrahepatic metastases. The protein products of genes known to be involved in molecular pathogenesis of HCC, including epidermal growth factor receptor (EGFR), MET, keratin 19 (K19), vimentin, beta-catenin, mechanistic target of rapamycin (mTOR), extracellular signaling-related RESULTS:Infection with hepatitis C virus was identified in 49% of the 80 autopsy patients, cirrhosis in 90%, advanced tumors in 95%, and extrahepatic metastases in 38%. Expression of K19, p53 and ERK1 correlated to high-grade lesions. Expression of ERK1, nuclear beta-catenin, cyclin D1 and ERK2 correlated to higher rates of cell proliferation as determined by Ki67. Expression of MET, EGFR (> 0) and caspase 3 correlated with lower histological grades. Expression of EGFR correlated to that of caspase 3, and overexpression of EGFR (≥ 200/300) was observed in low-grade tumors more frequently (grades 1 and 2: 67% vs grade 3: 27% and grade 4: 30%). Expression of ERK1 was associated with that of K19 and vimentin, whereas expression of ERK2 was associated with that of cyclin D1, MET and membrane beta-catenin. Expression of vimentin was strongly correlated with that of K19. CONCLUSION:Expression of K19, p53, ERK1, ERK2, vimentin and nuclear beta-catenin was related to highergrade markers, as opposed to expression/overexpression of EGFR, MET and caspase 3.

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“…ERK1/2 and phosphorylated ERK2 are increased in SNTA/B2−/− liver. This MAPK exerts various functions and its activity is enhanced by multiple stimuli [49] which will be identified in ongoing studies. Inhibition of ERK1/2 in primary hepatocytes induces SR-BI protein.…”

Section: Discussionmentioning

confidence: 99%

Lipid abnormalities in alpha/beta2-syntrophin null mice are independent from ABCA1

Hebel

Eisinger

Neumeier

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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The syntrophins alpha (SNTA) and beta 2 (SNTB2) are molecular adaptor proteins shown to stabilize ABCA1, an essential regulator of HDL cholesterol. Furthermore, SNTB2 is involved in glucose stimulated insulin release. Hyperglycemia and dyslipidemia are characteristic features of the metabolic syndrome, a serious public health problem with rising prevalence. Therefore, it is important to understand the role of the syntrophins herein. Mice deficient for both syntrophins (SNTA/B2−/−) have normal insulin and glucose tolerance, hepatic ABCA1 protein and cholesterol. When challenged with a HFD, wild type and SNTA/B2−/− mice have similar weight gain, adiposity, serum and liver triglycerides. Hepatic ABCA1, serum insulin and insulin sensitivity are normal while glucose tolerance is impaired. Liver cholesterol is reduced, and expression of SREBP2 and HMG-CoA-R is increased in the knockout mice. Scavenger receptor-BI (SR-BI) protein is strongly diminished in the liver of SNTA/B2−/− mice while SR-BI binding protein NHERF1 is not changed and PDZK1 is even induced. Knock-down of SNTA, SNTB2 or both has no effect on hepatocyte SR-BI and PDZK1 proteins. Further, SR-BI levels are not reduced in brown adipose tissue of SNTA/B2−/− mice excluding that syntrophins directly stabilize SR-BI. SR-BI stability is regulated by MAPK and phosphorylated ERK2 is induced in the liver of the knock-out mice. Blockage of ERK activity upregulates hepatocyte SR-BI showing that increased MAPK activity contributes to low SR-BI. Sphingomyelin which is well described to regulate cholesterol metabolism is reduced in the liver and serum of the knock-out mice while the size of serum lipoproteins is not affected. Current data exclude a major function of these syntrophins in ABCA1 activity and insulin release but suggest a role in regulating glucose uptake, ERK and SR-BI levels, and sphingomyelin metabolism in obesity.

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The MAPK MEK1/2-ERK1/2 Pathway and Its Implication in Hepatocyte Cell Cycle Control

Cited by 51 publications

References 152 publications

Proteomic Analysis of eIF5B Silencing-Modulated Proteostasis

Proteomic Analysis of eIF5B Silencing-Modulated Proteostasis

Immunohistochemistry panel segregates molecular types of hepatocellular carcinoma in Brazilian autopsy cases

Lipid abnormalities in alpha/beta2-syntrophin null mice are independent from ABCA1

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