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 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.

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 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 interacts with mRNA and the Nuclear RNA 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 ◽  
Vol 21 (1) ◽  
Author(s):  
Juan Manuel Iglesias-Pedraz ◽  
Diego Matia Fossatti-Jara ◽  
Valeria 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 interacts with mRNA and the Nuclear RNA 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.

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 Adenovirus Ubiquitin-Protein Ligase Stimulates Viral Late mRNA NuclearExport

2007 ◽  
Vol 81 (2) ◽  
pp. 575-587 ◽  
Author(s):  
Jennifer L. Woo ◽  
Arnold J. Berk
Keyword(s):  
Protein Synthesis ◽  
Nuclear Export ◽  
Mrna Export ◽  
Dominant Negative ◽  
Cellular Proteins ◽  
Mutant Form ◽  
Ubiquitin Protein Ligase ◽  
Mrn Complex ◽  
Early Protein ◽  
Cullin 5

ABSTRACT Theadenovirus type 5 (Ad5) E1B-55K and E4orf6 proteins are required together to stimulate viral late nuclear mRNA export to the cytoplasm and to restrict host cell nuclear mRNA export during the late phase of infection. Previous studies have shown that these two viral proteins interact with the cellular proteins elongins B and C, cullin 5, RBX1, and additional cellular proteins to form an E3 ubiquitin-protein ligase that polyubiquitinates p53 and probably one or more subunits of the MRE11-RAD50-NBS1 (MRN) complex, directing their proteasomal degradation. The MRN complex is required for cellular DNA double-strand break repair and induction of the DNA damage response by adenovirus infection. To determine if the ability of E1B-55K and E4orf6 to stimulate viral late mRNA nuclear export requires the ubiquitin-protein ligase activity of this viral ubiquitin-protein ligase complex, we designed and expressed a dominant-negative mutant form of cullin 5 in HeLa cells before infection with wild-type Ad5 or the E1B-55K null mutant dl1520. The dominant-negative cullin 5 protein stabilized p53 and the MRN complex, indicating that it inhibited the viral ubiquitin-protein ligase but had no effect on viral early mRNA synthesis, early protein synthesis, or viral DNA replication. However, expression of the dominant-negative cullin 5 protein caused a decrease in viral late protein synthesis and viral nuclear mRNA export similar to the phenotype produced by mutations in E1B-55K. We conclude that the stimulation of adenovirus late mRNA nuclear export by E1B-55K and E4orf6 results from the ubiquitin-protein ligase activity of the adenovirus ubiquitin-protein ligase complex.

scholarly journals Sensitization of FOLFOX-resistant colorectal cancer cells via the modulation of a novel pathway involving protein phosphatase 2A

2021 ◽  
Author(s):  
Satya Narayan ◽  
Asif Raza ◽  
Iqbal Mahmud ◽  
Nayeong Koo ◽  
Timothy Garrett ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Protein Synthesis ◽  
Cancer Cells ◽  
Small Molecule ◽  
Protein Phosphatase ◽  
Caspase 3 ◽  
Protein Phosphatase 2A ◽  
Global Protein Synthesis ◽  
Colorectal Cancer Cells ◽  
Phosphatase 2A

The treatment of colorectal cancer (CRC) with FOLFOX shows some efficacy, but these tumors quickly develop resistance to this treatment. We have observed an increased phosphorylation of AKT1/mTOR/4EBP1 and levels of p21 in FOLFOX-resistant CRC cells. We have identified a small molecule, NSC49L, that stimulates protein phosphatase 2A (PP2A) activity, downregulates the AKT1/mTOR/4EBP1-axis, and inhibits p21 translation. We have provided evidence that NSC49L- and TRAIL-mediated sensitization is synergistically induced in p21-knockdown CRC cells, which is reversed in p21-overexpressing cells. p21 binds with procaspase 3 and prevents activation of caspase 3. We have shown that TRAIL induces apoptosis through the activation of caspase 3 by NSC49L-mediated downregulation of p21 translation, and thereby cleavage of procaspase 3 into caspase 3. NSC49L does not affect global protein synthesis. These studies provide a mechanistic understanding of NSC49L as a PP2A agonist, and how its combination with TRAIL sensitizes FOLFOX-resistant CRC cells.

scholarly journals Base excision repair and its implications to cancer therapy

2020 ◽  
Vol 64 (5) ◽  
pp. 831-843 ◽  
Author(s):  
Gabrielle J. Grundy ◽  
Jason L. Parsons
Keyword(s):  
Oxidative Stress ◽  
Cancer Cells ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Repair Process ◽  
Loss Of Function ◽  
Strand Breaks ◽  
Single Strand Breaks ◽  
Base Excision ◽  
Integrity Of Dna

Abstract Base excision repair (BER) has evolved to preserve the integrity of DNA following cellular oxidative stress and in response to exogenous insults. The pathway is a coordinated, sequential process involving 30 proteins or more in which single strand breaks are generated as intermediates during the repair process. While deficiencies in BER activity can lead to high mutation rates and tumorigenesis, cancer cells often rely on increased BER activity to tolerate oxidative stress. Targeting BER has been an attractive strategy to overwhelm cancer cells with DNA damage, improve the efficacy of radiotherapy and/or chemotherapy, or form part of a lethal combination with a cancer specific mutation/loss of function. We provide an update on the progress of inhibitors to enzymes involved in BER, and some of the challenges faced with targeting the BER pathway.

scholarly journals Nucleoporin TPR promotes tRNA nuclear export and protein synthesis in lung cancer cells

PLoS Genetics ◽  
2021 ◽  
Vol 17 (11) ◽  
pp. e1009899
Author(s):  
Miao Chen ◽  
Qian Long ◽  
Melinda S. Borrie ◽  
Haohui Sun ◽  
Changlin Zhang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Protein Synthesis ◽  
Cancer Cells ◽  
Nuclear Export ◽  
Lung Cancer Cell ◽  
Imaging Strategy ◽  
Nuclear Export Protein ◽  
Cancer Tissues ◽  
Nascent Transcripts ◽  
Export Protein

The robust proliferation of cancer cells requires vastly elevated levels of protein synthesis, which relies on a steady supply of aminoacylated tRNAs. Delivery of tRNAs to the cytoplasm is a highly regulated process, but the machinery for tRNA nuclear export is not fully elucidated. In this study, using a live cell imaging strategy that visualizes nascent transcripts from a specific tRNA gene in yeast, we identified the nuclear basket proteins Mlp1 and Mlp2, two homologs of the human TPR protein, as regulators of tRNA export. TPR expression is significantly increased in lung cancer tissues and correlated with poor prognosis. Consistently, knockdown of TPR inhibits tRNA nuclear export, protein synthesis and cell growth in lung cancer cell lines. We further show that NXF1, a well-known mRNA nuclear export factor, associates with tRNAs and mediates their transport through nuclear pores. Collectively, our findings uncover a conserved mechanism that regulates nuclear export of tRNAs, which is a limiting step in protein synthesis in eukaryotes.

scholarly journals Quantitative Proteomic Profiling Identifies a Potential Novel Chaperone Marker in Resistant Breast Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Karen M. Gallegos ◽  
Jankiben R. Patel ◽  
Shawn D. Llopis ◽  
Rashidra R. Walker ◽  
A. Michael Davidson ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Protein Synthesis ◽  
Aromatase Inhibitor ◽  
Cancer Cells ◽  
Nuclear Export ◽  
Breast Cancer Cells ◽  
Endocrine Resistance ◽  
Functional Enrichment ◽  
Breast Cancer Cell Lines ◽  
Mesenchymal Transition

Development of aromatase inhibitor resistant breast cancer among postmenopausal women continues to be a major clinical obstacle. Previously, our group demonstrated that as breast cancer cells transition from hormone-dependent to hormone-independent, they are associated with increased growth factor signaling, enhanced cellular motility, and the epithelial to mesenchymal transition (EMT). Given the complexity of cancer stem cells (CSC) and their implications on endocrine resistance and EMT, we sought to understand their contribution towards the development of aromatase inhibitor resistant breast cancer. Cells cultured three dimensionally as mammospheres are enriched for CSCs and more accurately recapitulates tumors in vivo. Therefore, a global proteomic analysis was conducted using letrozole resistant breast cancer cells (LTLT-Ca) mammospheres and compared to their adherent counterparts. Results demonstrated over 1000 proteins with quantitative abundance ratios were identified. Among the quantified proteins, 359 were significantly altered (p < 0.05), where 173 were upregulated and 186 downregulated (p < 0.05, fold change >1.20). Notably, midasin, a chaperone protein required for maturation and nuclear export of the pre-60S ribosome was increased 35-fold. Protein expression analyses confirmed midasin is ubiquitously expressed in normal tissue but is overexpressed in lobular and ductal breast carcinoma tissue as well as ER+ and ER- breast cancer cell lines. Functional enrichment analyses indicated that 19 gene ontology terms and one KEGG pathway were over-represented by the down-regulated proteins and both were associated with protein synthesis. Increased midasin was strongly correlated with decreased relapse free survival in hormone independent breast cancer. For the first time, we characterized the global proteomic signature of CSC-enriched letrozole-resistant cells associated with protein synthesis, which may implicate a role for midasin in endocrine resistance.

Sign in / Sign up

Export Citation Format

Share Document