scholarly journals Mechanical Forces and Their Effect on the Ribosome and Protein Translation Machinery

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 650 ◽  
Author(s):  
Lisa J. Simpson ◽  
Ellie Tzima ◽  
John S. Reader
Keyword(s):  
Messenger Rna ◽  
Protein Translation ◽  
Cellular Level ◽  
Mechanical Forces ◽  
Active Protein ◽  
Translation Machinery ◽  
Translational Machinery ◽  
Naturally Occurring ◽  
Bacterial Ribosome ◽  
Cellular Phenotypes

Mechanical forces acting on biological systems, at both the macroscopic and microscopic levels, play an important part in shaping cellular phenotypes. There is a growing realization that biomolecules that respond to force directly applied to them, or via mechano-sensitive signalling pathways, can produce profound changes to not only transcriptional pathways, but also in protein translation. Forces naturally occurring at the molecular level can impact the rate at which the bacterial ribosome translates messenger RNA (mRNA) transcripts and influence processes such as co-translational folding of a nascent protein as it exits the ribosome. In eukaryotes, force can also be transduced at the cellular level by the cytoskeleton, the cell’s internal filamentous network. The cytoskeleton closely associates with components of the translational machinery such as ribosomes and elongation factors and, as such, is a crucial determinant of localized protein translation. In this review we will give (1) a brief overview of protein translation in bacteria and eukaryotes and then discuss (2) how mechanical forces are directly involved with ribosomes during active protein synthesis and (3) how eukaryotic ribosomes and other protein translation machinery intimately associates with the mechanosensitive cytoskeleton network.

scholarly journals Suppression of Global Protein Translation in SARS-CoV-2 Infection

2021 ◽  
Author(s):  
Haripriya Parthasarathy ◽  
Divya Gupta ◽  
Abhirami P Suresh ◽  
Dixit Tandel ◽  
Vishal Sah ◽  
...  
Keyword(s):  
Ribosomal Proteins ◽  
Critical Role ◽  
Protein Translation ◽  
Potential Contribution ◽  
Strong Suppression ◽  
Translational Machinery ◽  
Polysome Profiling ◽  
Viral Survival ◽  
Global Translation ◽  
Viral Titers

The relationship of SARS-CoV-2 with the host translation remains largely unexplored. Using polysome profiling of SARS-CoV-2 infected Caco2 cells, we here demonstrate that the virus induces a strong suppression of global translation by 48 hours of infection. Heavy polysome fractions displayed substantial depletion in the infected cells, indicating the loss of major translational activities in them. Further assessment of the major pathways regulating translation in multiple permissive cell lines revealed strong eIF4E dephosphorylation accompanied by Mnk1 depletion and ERK1/2 dephosphorylations. p38MAPK showed consistent activation and its inhibition lowered viral titers, indicating its importance in viral survival. No significant change was noticed in eIF2 α phosphorylation. mTORC1 pathway showed the most profound inhibition, indicating its potential contribution to the suppression of global translation associated with the infection. Pharmacological activation of mTORC1 caused a drop in viral titers while inhibition resulted in higher viral RNA levels, confirming a critical role of mTORC1 in regulating viral replication. Surprisingly, the infection did not cause a general suppression of 5′-TOP translation, as evident from the continued expression of ribosomal proteins. Our results collectively indicate that the differential suppression of mTORC1 might allow SARS-CoV-2 to hijack translational machinery in its favor and specifically target a set of host mRNAs.

scholarly journals Chemotherapy Resistance in Advanced Ovarian Cancer Patients

2019 ◽  
Vol 11 ◽  
pp. 1179299X1986081 ◽  
Author(s):  
Ruchika Pokhriyal ◽  
Roopa Hariprasad ◽  
Lalit Kumar ◽  
Gururao Hariprasad
Keyword(s):  
Ovarian Cancer ◽  
Messenger Rna ◽  
Chemotherapy Resistance ◽  
Advanced Ovarian Cancer ◽  
Cellular Level ◽  
Chemotherapy Response ◽  
First Line ◽  
Debulking Surgery ◽  
Standard Management ◽  
Gynaecologic Malignancy

Ovarian cancer is the seventh most common gynaecologic malignancy seen in women. Majority of the patients with ovarian cancer are diagnosed at the advanced stage making prognosis poor. The standard management of advanced ovarian cancer includes tumour debulking surgery followed by chemotherapy. Various types of chemotherapeutic regimens have been used to treat advanced ovarian cancer, but the most promising and the currently used standard first-line treatment is carboplatin and paclitaxel. Despite improved clinical response and survival to this combination of chemotherapy, numerous patients either undergo relapse or succumb to the disease as a result of chemotherapy resistance. To understand this phenomenon at a cellular level, various macromolecules such as DNA, messenger RNA and proteins have been developed as biomarkers for chemotherapy response. This review comprehensively summarizes the problem that pertains to chemotherapy resistance in advanced ovarian cancer and provides a good overview of the various biomarkers that have been developed in this field.

Potentiation of CD3-induced expression of the linker for activation of T cells (LAT) by the calcineurin inhibitors cyclosporin A and FK506

Blood ◽  
2000 ◽  
Vol 95 (9) ◽  
pp. 2733-2741 ◽  
Author(s):  
David Peters ◽  
Masahiro Tsuchida ◽  
Eric R. Manthei ◽  
Tausif Alam ◽  
Clifford S. Cho ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cyclosporin A ◽  
T Cell Activation ◽  
Messenger Rna ◽  
Cell Activation ◽  
Calcineurin Inhibitors ◽  
Northern Blotting ◽  
Cellular Level ◽  
Therapeutic Implications

The activation of blood cells, including T cells, triggers intracellular signals that control the expression of critical molecules, including cytokines and cytokine receptors. We show that T-cell receptor (TCR) ligation increases the cellular level of the protein linker for activation of T cells (LAT), a molecule critical for T-cell development and function. T-cell activation increased LAT messenger RNA, as determined by reverse transcription–polymerase chain reaction and by Northern blotting. The TCR-induced increase in LAT expression involved the activation of the serine/threonine kinases PKC and MEK, because inhibitors of these kinases blocked the increase in LAT. Accordingly, the PKC activator phorbol myristate acetate up-regulated LAT expression. Strikingly, the calcineurin inhibitors cyclosporin A (CsA) and FK506 strongly potentiated TCR-induced LAT expression, suggesting that the activation of calcineurin following TCR ligation negatively regulates LAT expression. Accordingly, Ca++ ionophores, which can activate calcineurin by increasing intracellular Ca++, blocked the TCR-induced increase in cellular LAT. CsA and FK506 blocked the Ca++ionophores' inhibitory effect on LAT expression. Notably, CsA and FK506 preferentially up-regulated TCR-induced LAT expression; under the same conditions, these compounds did not increase the expression of 14 other molecules that previously had been implicated in T-cell activation. These data show that TCR-induced LAT expression involves the activation of the PKC-Erk pathway and is negatively regulated by the activation of calcineurin. Furthermore, the potentiation of TCR-induced LAT expression by CsA and FK506 suggests that the action of these agents involves up-regulating the cellular level of critical signaling molecules. These findings may have important therapeutic implications.

scholarly journals MicroRNA-223-3p inhibits human bladder cancer cell migration and invasion

Tumor Biology ◽  
2017 ◽  
Vol 39 (2) ◽  
pp. 101042831769167 ◽  
Author(s):  
Ju Guo ◽  
Runfu Cao ◽  
Xingwei Yu ◽  
Zewen Xiao ◽  
Zhiwen Chen
Keyword(s):  
Nuclear Receptor ◽  
Bladder Carcinoma ◽  
Messenger Rna ◽  
Tumor Tissue ◽  
Protein Translation ◽  
Carcinoma Cells ◽  
Migration And Invasion ◽  
Nuclear Receptor Coactivator ◽  
Bladder Carcinoma Cells

The regulation of initiation and progression during carcinogenesis of bladder carcinoma is not completely elucidated. Dysregulation of microRNAs has been detected to play critical roles in the development of various cancers, including bladder carcinoma, whereas the involvement of miR-223-3p in the tumorigenesis of bladder carcinoma has not been studied. Here, we show that significantly higher levels of nuclear receptor coactivator 1 and significantly lower levels of miR-223-3p were detected in bladder carcinoma tissue, compared to the adjacent non-tumor tissue. In addition, the levels of nuclear receptor coactivator 1 and miR-223-3p were inversely correlated. Moreover, low miR-223-3p levels in bladder carcinoma specimens were associated with poor prognosis. In vitro, depletion of miR-223-3p increased bladder carcinoma cell invasion, which was abolished by overexpression of nuclear receptor coactivator 1. Bioinformatics studies demonstrate that miR-223-3p may bind to the 3′-UTR of nuclear receptor coactivator 1 messenger RNA to inhibit its protein translation in bladder carcinoma cells. Together, our study highlights miR-223-3p as a previously unrecognized microRNA that inhibits bladder carcinoma invasiveness via nuclear receptor coactivator 1, and this finding may be important for developing innovative therapeutic targets in treating bladder carcinoma.

scholarly journals Expression of IMP dehydrogenase in differentiating HL-60 cells

Blood ◽  
1990 ◽  
Vol 75 (3) ◽  
pp. 570-576 ◽  
Author(s):  
FR Collart ◽  
E Huberman
Keyword(s):  
Cell Differentiation ◽  
Mycophenolic Acid ◽  
Messenger Rna ◽  
Cellular Level ◽  
Imp Dehydrogenase ◽  
Protein Levels ◽  
Impdh Activity ◽  
Subsequent Decrease ◽  
Number Of Factors ◽  
Steady State Levels

Abstract Addition of mycophenolic acid to cultures of HL-60 cells results in a decreased cellular level of guanine nucleotides and the induction of cell differentiation. During the early stages of this induction, steady- state levels of cellular IMP dehydrogenase (IMPDH), messenger RNA (mRNA), and protein are increased, perhaps because of cellular compensation for the inhibition of IMPDH activity. The subsequent decrease in IMPH mRNA and protein levels after several days of treatment suggests a change in the control of IMPDH expression. In contrast to the pattern of increased IMPDH expression observed in the mycophenolic acid-treated cells, treatment of HL-60 cells with two other inducers of differentiation, namely retinoic acid and phorbol 12- myristate 13-acetate, resulted in stable or decreased levels of cellular IMPDH mRNA and protein. However, the kinetics of this expression were different. These results suggest that a number of factors influence the regulation of IMPDH expression during the induction of HL-60 cell differentiation, including the nature of the inducer. A decrease in the cellular IMPDH activity was observed for all of the inducers, suggesting that this decreased activity may be a determining factor in the acquisition of a mature phenotype in the HL- 60 cells.

scholarly journals PRP4K is a haploinsufficient tumour suppressor negatively regulated during epithelial-to-mesenchymal transition

2020 ◽  
Author(s):  
Livia E. Clarke ◽  
Carter Van Iderstine ◽  
Sabateeshan Mathavarajah ◽  
Amit Bera ◽  
Moamen Bydoun ◽  
...  
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Essential Gene ◽  
Protein Translation ◽  
Mammary Epithelial ◽  
Tumour Suppressor ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Tumour Suppressor Genes ◽  
Mesenchymal Transition ◽  
Cellular Phenotypes

ABSTRACTReduced expression of haploinsufficient tumour suppressor genes is sufficient to alter cellular phenotypes towards carcinogenesis without complete loss of gene expression. As an essential gene, complete expression loss of pre-mRNA processing factor 4 kinase (PRP4K, also known as PRPF4B) is lethal. However, we demonstrate here that reduction of PRP4K levels by small interfering RNA in the mammary epithelial cell lines HMLE and MCF10A can induce partial epithelial-to-mesenchymal transition (EMT) marked by the retention of epithelial markers such as Zo-1 and E-cadherin, and upregulation of mesenchymal markers such as fibronectin and Zeb1. This partial EMT phenotype in non-transformed PRP4K-depleted cells is associated with greater invasive potential in 3D transwell assays, but either reduces or has no effect on 2D migration examined by scratch assay. This is in contrast to depletion of PRP4K in transformed triple-negative MDA-MB-231 breast cancer cells, which results in enhanced migration in 2D and invasion in 3D. Induction of EMT, using EMT-inducing media containing WNT-5a and TGF-β1 or depletion of eukaryotic translation initiation factor 3e (eIF3e) by shRNA, results in marked reduction of PRP4K expression. EMT induced by eIF3e depletion does not affect the transcription of PRP4K mRNA or turn-over of PRP4K protein, but rather reduces its protein translation. Finally, reduced PRP4K levels after eIF3e depletion correlated with increased YAP activity and nuclear localization, the latter being reversed by overexpression of exogenous PRP4K. Together, these data indicate that PRP4K is a haploinsufficient tumour suppressor negatively regulated by EMT, and that when depleted can induce partial EMT and increased cell invasion.

scholarly journals The Great Escape: mRNA Export through the Nuclear Pore Complex

2021 ◽  
Vol 22 (21) ◽  
pp. 11767
Author(s):  
Paola De Magistris
Keyword(s):  
Conformational Changes ◽  
Nuclear Pore Complex ◽  
Nuclear Export ◽  
Messenger Rna ◽  
Mrna Export ◽  
Protein Translation ◽  
Nuclear Pore ◽  
Body Of Knowledge ◽  
Transport Receptors ◽  
Basic Characteristics

Nuclear export of messenger RNA (mRNA) through the nuclear pore complex (NPC) is an indispensable step to ensure protein translation in the cytoplasm of eukaryotic cells. mRNA is not translocated on its own, but it forms ribonuclear particles (mRNPs) in association with proteins that are crucial for its metabolism, some of which; like Mex67/MTR2-NXF1/NXT1; are key players for its translocation to the cytoplasm. In this review, I will summarize our current body of knowledge on the basic characteristics of mRNA export through the NPC. To be granted passage, the mRNP cargo needs to bind transport receptors, which facilitate the nuclear export. During NPC transport, mRNPs undergo compositional and conformational changes. The interactions between mRNP and the central channel of NPC are described; together with the multiple quality control steps that mRNPs undergo at the different rings of the NPC to ensure only proper export of mature transcripts to the cytoplasm. I conclude by mentioning new opportunities that arise from bottom up approaches for a mechanistic understanding of nuclear export.

scholarly journals SAMD9L autoinflammatory or ataxia pancytopenia disease mutations activate cell-autonomous translational repression

2021 ◽  
Vol 118 (34) ◽  
pp. e2110190118
Author(s):  
Amanda J. Russell ◽  
Paul E. Gray ◽  
John B. Ziegler ◽  
Yae Jean Kim ◽  
Sandy Smith ◽  
...  
Keyword(s):  
Messenger Rna ◽  
Autoinflammatory Disease ◽  
Fluorescent Protein ◽  
Single Cell Analysis ◽  
De Novo ◽  
Protein Translation ◽  
Translational Repression ◽  
Translational Repressor ◽  
Activate Cell ◽  
Green Fluorescent

Sterile α motif domain-containing protein 9-like (SAMD9L) is encoded by a hallmark interferon-induced gene with a role in controlling virus replication that is not well understood. Here, we analyze SAMD9L function from the perspective of human mutations causing neonatal-onset severe autoinflammatory disease. Whole-genome sequencing of two children with leukocytoclastic panniculitis, basal ganglia calcifications, raised blood inflammatory markers, neutrophilia, anemia, thrombocytopaenia, and almost no B cells revealed heterozygous de novo SAMD9L mutations, p.Asn885Thrfs*6 and p.Lys878Serfs*13. These frameshift mutations truncate the SAMD9L protein within a domain a region of homology to the nucleotide-binding and oligomerization domain (NOD) of APAF1, ∼80 amino acids C-terminal to the Walker B motif. Single-cell analysis of human cells expressing green fluorescent protein (GFP)-SAMD9L fusion proteins revealed that enforced expression of wild-type SAMD9L repressed translation of red fluorescent protein messenger RNA and globally repressed endogenous protein translation, cell autonomously and in proportion to the level of GFP-SAMD9L in each cell. The children’s truncating mutations dramatically exaggerated translational repression even at low levels of GFP-SAMD9L per cell, as did a missense Arg986Cys mutation reported recurrently as causing ataxia pancytopenia syndrome. Autoinflammatory disease associated with SAMD9L truncating mutations appears to result from an interferon-induced translational repressor whose activity goes unchecked by the loss of C-terminal domains that may normally sense virus infection.

MATERNAL mRNA AND PROTEIN SYNTHESIS IN THE EMBRYO

1973 ◽  
Vol 74 (Suppl) ◽  
pp. S244-S262 ◽  
Author(s):  
P. R. Gross ◽  
K. W. Gross ◽  
A. I. Skoultchi ◽  
J. V. Ruderman
Keyword(s):  
Protein Synthesis ◽  
Sea Urchin ◽  
Messenger Rna ◽  
Direct Proof ◽  
Indirect Evidence ◽  
Translation Control ◽  
Histone Mrna ◽  
Translational Machinery ◽  
Maternal Mrna ◽  
Histone Synthesis

ABSTRACT According to the masked maternal messenger RNA hypothesis, a large part if not all the protein synthesis of early development is directed by mRNA already present in the cytoplasm of unfertilized eggs. This mRNA is supposed to be synthesized during oogenesis and stored in some unavailable form until some later time in development, when it is selectively associated with the translational machinery. To the indirect evidence, which is nevertheless very strong, there can now be added a direct proof of the hypothesis for the case of histone mRNA. The five main histones of sea urchin embryos are synthesized on small polyribosomes, directed in part by newly-synthesized messages that sediment as a group at about 9S. Some histone synthesis survives total transcription block, however, suggesting that maternal histone mRNA exists. In competition-hybridization experiments, the egg RNA is shown to contain sequences characteristic of functional, embryonic histone mRNA. The competing RNA is localized in ribonucleoprotein particles of egg homogenates that sediment at 20–40S. These same particles contain RNA that stimulates a cell-free heterologous system to synthesize sea urchin histones. The application of these facts to some problems of translation control and of development generally is discussed.

scholarly journals MicroRNA Role in Thyroid Cancer Development

2011 ◽  
Vol 2011 ◽  
pp. 1-12 ◽  
Author(s):  
Francesca Marini ◽  
Ettore Luzi ◽  
Maria Luisa Brandi
Keyword(s):  
Thyroid Cancer ◽  
Messenger Rna ◽  
Noncoding Rnas ◽  
Protein Translation ◽  
Cancer Development ◽  
Regulate Gene Expression ◽  
Rna Targets ◽  
Mirna Deregulation ◽  
Cell Maintenance

MicroRNAs (miRNAs) are endogenous noncoding RNAs that negatively regulate gene expression by binding the 3′noncoding region of the messenger RNA targets inducing their cleavage or blocking the protein translation. They play important roles in multiple biological and metabolic processes, including developmental timing, signal transduction, and cell maintenance and differentiation. Their deregulation can predispose to diseases and cancer. miRNA expression has been demonstrated to be deregulated in many types of human tumors, including thyroid cancers, and could be responsible for tumor initiation and progression. In this paper we reviewed the available data on miRNA deregulation in different thyroid tumors and describe the putative role of miRNA in thyroid cancer development.

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