Pharmacologic inhibition of the CK2-mediated phosphorylation of B23/NPM in cancer cells selectively modulates genes related to protein synthesis, energetic metabolism, and ribosomal biogenesis

2015 ◽  
Vol 404 (1-2) ◽  
pp. 103-112 ◽  
Author(s):  
Yasser Perera ◽  
Seidy Pedroso ◽  
Orlando Borras-Hidalgo ◽  
Dania M. Vázquez ◽  
Jamilet Miranda ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Cancer Cells ◽  
Ribosomal Biogenesis ◽  
Energetic Metabolism ◽  
Pharmacologic Inhibition

scholarly journals Molecular alterations after Polo-like kinase 1 mRNA suppression versus pharmacologic inhibition in cancer cells

2006 ◽  
Vol 5 (4) ◽  
pp. 809-817 ◽  
Author(s):  
Mathias Schmidt ◽  
Hans-Peter Hofmann ◽  
Karl Sanders ◽  
Georg Sczakiel ◽  
Thomas L. Beckers ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Molecular Alterations ◽  
Pharmacologic Inhibition

Abstract P238: Regulation Of G Protein-coupled Receptor Kinase 4 Expression By Serum In Breast Cancer And Renal Proximal Tubule Cells

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Wei Yue ◽  
Peng Xu ◽  
John J Gildea ◽  
Robin A Felder
Keyword(s):  
Breast Cancer ◽  
Protein Synthesis ◽  
Proximal Tubule ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Renal Proximal Tubule ◽  
Proximal Tubule Cells ◽  
Tubule Cells ◽  
Renal Proximal Tubule Cells ◽  
G Protein Coupled

G protein-coupled receptor kinase 4 (GRK4) is a member of the GRK family which play critical role in regulation of the function of G protein-coupled receptors. Our previous studies have shown that GRK4 not only plays a role in regulating sodium excretion in renal proximal tubule cells but also acts as a stimulator on proliferation of breast cancer cells. Uncontrolled proliferation is a characteristics of cancer cells and GRK4 is upregulated in breast cancer cells. We hypothesized that expression of GRK4 may be regulated differently in cancer and non-cancer cells. To test this hypothesis, expression of GRK4 in response to serum was compared in breast cancer cells and renal proximal tubule cells by Western analysis. In three breast cancer cell lines serum withdrawal caused rapid reduction in the levels of GRK4 which occurred as early as 15 min. GRK4 levels correlated with the concentrations of serum added to the culture media. To determine if growth factors were a critical element for maintaining GRK4 levels in the cells, EGF (10-20 ng/ml) was added to serum free medium for 24 h. There was no increase in GRK4 levels in the cells treated with EGF compared with the serum starvation control. Similarly, serum withdrawal (16 h) led to 40-80% decrease of GRK4 levels in renal proximal tubule cells even in the presence of EFG supplement. Serum feeding for 30 min after starvation dramatically increased the levels of GRK4 in both breast cancer cells and RPTC which exceeded the steady state levels. This rapid recovery of GRK4 protein do not need de novo protein synthesis because pretreatment of the cells with protein synthesis inhibitor, cycloheximide (10 μg/ml, 24 h), did not prevent this event. Expression of GRK2, another member of the GRK family, was not affected by serum starvation. Our results have shown that GRK4 is very sensitive to serum concentration in breast cancer cells as well as in RPTC. Preliminary studies suggest that rapid protein degradation rather than shutting down the protein synthesis plays a major role in this kind of GRK4 regulation. The biological significance of serum regulation of GRK4 in cancer and non-cancerous cells needs further investigation.

scholarly journals WRN modulates translation by influencing mRNA export from the nucleus through its interaction with the export receptor NXF1 in HeLa cancer cell

2020 ◽  
Author(s):  
Juan Manuel Iglesias-Pedraz ◽  
Diego Matia Fossatti Jara ◽  
Valeria Del Carmen Valle-Riestra Felice ◽  
Sergio Rafael Cruz Visalaya ◽  
Jose Antonio Ayala Felix ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Protein Synthesis ◽  
Cancer Cells ◽  
Nuclear Export ◽  
Werner Syndrome ◽  
Mrna Export ◽  
Premature Aging ◽  
Metabolic Shift ◽  
Loss Of Function ◽  
Global Protein Synthesis

Abstract Background The Werner syndrome protein (WRN) belongs to the RecQ family of helicases and its loss of function results in the premature aging disease Werner syndrome (WS). We previously demonstrated that an early cellular change induced by WRN depletion is a posttranscriptional decrease in the levels of enzymes involved in metabolic pathways that control macromolecular synthesis and protect from oxidative stress. This metabolic shift is tolerated by normal cells but causes mitochondria dysfunction and acute oxidative stress in rapidly growing cancer cells, thereby suppressing their proliferation.Results To identify the mechanism underlying this metabolic shift, we examined global protein synthesis and mRNA nucleocytoplasmic distribution after WRN knockdown. We determined that WRN depletion in HeLa cells attenuates global protein synthesis without affecting the level of key components of the mRNA export machinery. We further observed that WRN depletion affects the nuclear export of mRNAs and demonstrated that WRN directly interacts with mRNA and the mRNA export receptor Nuclear Export Factor 1 (NXF1).Conclusions Our findings suggest that WRN influences the export of mRNAs from the nucleus through its interaction with the NXF1 export receptor thereby affecting cellular proteostasis. In summary, we identified a new partner and a novel function of WRN, which is especially important for the proliferation of cancer cells.

scholarly journals WRN modulates mRNA translation by influencing mRNA export from the nucleus through its interaction with the export receptor NXF1 in HeLa cancer cell

2020 ◽  
Author(s):  
Juan Manuel Iglesias-Pedraz ◽  
Diego Matia Fossatti Jara ◽  
Valeria Del Carmen Valle-Riestra Felice ◽  
Sergio Rafael Cruz Visalaya ◽  
Jose Antonio Ayala Felix ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Protein Synthesis ◽  
Cancer Cells ◽  
Nuclear Export ◽  
Werner Syndrome ◽  
Mrna Export ◽  
Mrna Translation ◽  
Premature Aging ◽  
Metabolic Shift ◽  
Global Protein Synthesis

Abstract BackgroundThe Werner syndrome protein (WRN) belongs to the RecQ family of helicases and its loss of function results in the premature aging disease Werner syndrome (WS). We previously demonstrated that an early cellular change induced by WRN depletion is a posttranscriptional decrease in the levels of enzymes involved in metabolic pathways that control macromolecular synthesis and protect from oxidative stress. This metabolic shift is tolerated by normal cells but causes mitochondria dysfunction and acute oxidative stress in rapidly growing cancer cells, thereby suppressing their proliferation.Results To identify the mechanism underlying this metabolic shift, we examined global protein synthesis and mRNA nucleocytoplasmic distribution after WRN knockdown. We determined that WRN depletion in HeLa cells attenuates global protein synthesis without affecting the level of key components of the mRNA export machinery. We further observed that WRN depletion affects the nuclear export of mRNAs and demonstrated that WRN directly interacts with mRNA and the mRNA export receptor Nuclear Export Factor 1 (NXF1).Conclusions Our findings suggest that WRN influences the export of mRNAs from the nucleus through its interaction with the NXF1 export receptor thereby affecting cellular proteostasis. In summary, we identified a new partner and a novel function of WRN, which is especially important for the proliferation of cancer cells.

scholarly journals WRN modulates translation by influencing nuclear mRNA export in HeLa cancer cells

2020 ◽  
Author(s):  
Juan Manuel Iglesias-Pedraz ◽  
Diego Matia Fossatti Jara ◽  
Valeria Del Carmen Valle-Riestra Felice ◽  
Sergio Rafael Cruz Visalaya ◽  
Jose Antonio Ayala Felix ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Protein Synthesis ◽  
Cancer Cells ◽  
Nuclear Export ◽  
Werner Syndrome ◽  
Mrna Export ◽  
Premature Aging ◽  
Metabolic Shift ◽  
Loss Of Function ◽  
Global Protein Synthesis

Abstract BackgroundThe Werner syndrome protein (WRN) belongs to the RecQ family of helicases and its loss of function results in the premature aging disease Werner syndrome (WS). We previously demonstrated that an early cellular change induced by WRN depletion is a posttranscriptional decrease in the levels of enzymes involved in metabolic pathways that control macromolecular synthesis and protect from oxidative stress. This metabolic shift is tolerated by normal cells but causes mitochondria dysfunction and acute oxidative stress in rapidly growing cancer cells, thereby suppressing their proliferation.ResultsTo identify the mechanism underlying this metabolic shift, we examined global protein synthesis and mRNA nucleocytoplasmic distribution after WRN knockdown. We determined that WRN depletion in HeLa cells attenuates global protein synthesis without affecting the level of key components of the mRNA export machinery. We further observed that WRN depletion affects the nuclear export of mRNAs and demonstrated that WRN interacts with mRNA and the Nuclear RNA Export Factor 1 (NXF1).ConclusionsOur findings suggest that WRN influences the export of mRNAs from the nucleus through its interaction with the NXF1 export receptor thereby affecting cellular proteostasis. In summary, we identified a new partner and a novel function of WRN, which is especially important for the proliferation of cancer cells.

Direct Evidence of the Link Between Energetic Metabolism and Proliferation Capacity of Cancer Cells In Vitro

2016 ◽  
pp. 209-214 ◽  
Author(s):  
Géraldine De Preter ◽  
Pierre Danhier ◽  
Paolo E. Porporato ◽  
Valéry L. Payen ◽  
Bénédicte F. Jordan ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Direct Evidence ◽  
Energetic Metabolism ◽  
Proliferation Capacity

Abstract 22: Crosstalk Between Phosphotidylinositol-4,5 Bisphosphonate-3 Kinase Pathway and Mitogen-Activated Protein Kinase Pathway Regulates Platelet Activation and Protein Synthesis via Phosphoinositide-Dependent Kinase-1

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Bhanu Kanth Manne ◽  
Patrick Münzer ◽  
Rachit Badolia ◽  
Andrew S. Weyrich ◽  
Satya P Kunapuli ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Protein Kinase ◽  
Platelet Activation ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Genetic Ablation ◽  
Upstream Kinase ◽  
Dependent Protein ◽  
Kinase Pathway ◽  
Pharmacologic Inhibition

Phosphoinositide-dependent protein kinase 1 (PDK1) is known to regulate PAR4 induced platelet activation and thrombus formation through GSK3β. However, whether PDK1 signaling also involves the ADP receptor and, if so, downstream functional consequences are unknown. We employed both pharmacologic (e.g. the selective PDK1 inhibitor, BX795) and genetic (platelet specific deletion of PDK1) approaches to dissect the role of PDK1 in ADP-induced platelet activation and protein synthesis. Inhibition of PDK1 with BX795 reduced 2MeSADP-induced platelet aggregation by abolishing thromboxane generation. Similar results were observed in PDK1 -/- mice (Fig A). Inhibition of PDK1 protected mice from collagen and epinephrine-induced pulmonary embolism (Fig B). PDK1 was also necessary for the phosphorylation of MEK1/2, Erk1/2 and cPLA2, indicating that PDK1 regulates an upstream kinase in MAPK pathway. We next identified that this upstream kinase is Raf1 (necessary for the phosphorylation of MEK1/2), as pharmacologic inhibition and genetic ablation of PDK1 was sufficient to prevent Raf1 phosphorylation (Fig C). Pharmacologic inhibition and genetic ablation of PDK1 blocked MAPK- and mTORC1-dependent protein synthesis in platelets through a mechanism requiring the phosphorylation of eIF4E and S6K. Concordantly, PDK1 is necessary for signal-dependent synthesis of the protein bcl3, which is under mTORC1-dependent control (Fig C). Taken together, our findings show for the first time that PDK1, a master kinase in the PI3K pathway, directly governs thromboxane generation, thrombosis, and protein synthesis in platelets through regulating MAPK and mTORC1 pathways.

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