scholarly journals Rpl24Bst mutation suppresses colorectal cancer by promoting eEF2 phosphorylation via eEF2K

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
John RP Knight ◽  
Nikola Vlahov ◽  
David M Gay ◽  
Rachel A Ridgway ◽  
William Liam Faller ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Protein Synthesis ◽  
Mouse Models ◽  
Mutant Mouse ◽  
Effective Means ◽  
Ribosomal Subunit ◽  
Suppressive Effect ◽  
Driver Mutations ◽  
Translation Elongation ◽  
Colorectal Tumorigenesis

Increased protein synthesis supports the rapid cell proliferation associated with cancer. The Rpl24Bst mutant mouse reduces the expression of the ribosomal protein RPL24 and has been used to suppress translation and limit tumorigenesis in multiple mouse models of cancer. Here, we show that Rpl24Bst also suppresses tumorigenesis and proliferation in a model of colorectal cancer (CRC) with two common patient mutations, Apc and Kras. In contrast to previous reports, Rpl24Bst mutation has no effect on ribosomal subunit abundance but suppresses translation elongation through phosphorylation of eEF2, reducing protein synthesis by 40% in tumour cells. Ablating eEF2 phosphorylation in Rpl24Bst mutant mice by inactivating its kinase, eEF2K, completely restores the rates of elongation and protein synthesis. Furthermore, eEF2K activity is required for the Rpl24Bst mutant to suppress tumorigenesis. This work demonstrates that elevation of eEF2 phosphorylation is an effective means to suppress colorectal tumorigenesis with two driver mutations. This positions translation elongation as a therapeutic target in CRC, as well as in other cancers where the Rpl24Bst mutation has a tumour suppressive effect in mouse models.

scholarly journals A Complementary Mechanism of Bacterial mRNA Translation Inhibition by Tetracyclines

2021 ◽  
Vol 12 ◽  
Author(s):  
Victor Barrenechea ◽  
Maryhory Vargas-Reyes ◽  
Miguel Quiliano ◽  
Pohl Milón
Keyword(s):  
Protein Synthesis ◽  
Translation Initiation ◽  
Ribosomal Subunit ◽  
Mrna Translation ◽  
Resistance Mechanisms ◽  
Dissociation Rate ◽  
Initiation Factor ◽  
Translation Elongation ◽  
Initiation Phase ◽  
Complementary Mechanism

Tetracycline has positively impacted human health as well as the farming and animal industries. Its extensive usage and versatility led to the spread of resistance mechanisms followed by the development of new variants of the antibiotic. Tetracyclines inhibit bacterial growth by impeding the binding of elongator tRNAs to the ribosome. However, a small number of reports indicated that Tetracyclines could also inhibit translation initiation, yet the molecular mechanism remained unknown. Here, we use biochemical and computational methods to study how Oxytetracycline (Otc), Demeclocycline (Dem), and Tigecycline (Tig) affect the translation initiation phase of protein synthesis. Our results show that all three Tetracyclines induce Initiation Factor IF3 to adopt a compact conformation on the 30S ribosomal subunit, similar to that induced by Initiation Factor IF1. This compaction was faster for Tig than Dem or Otc. Furthermore, all three tested tetracyclines affected IF1-bound 30S complexes. The dissociation rate constant of IF1 in early 30S complexes was 14-fold slower for Tig than Dem or Otc. Late 30S initiation complexes (30S pre-IC or IC) exhibited greater IF1 stabilization by Tig than for Dem and Otc. Tig and Otc delayed 50S joining to 30S initiation complexes (30S ICs). Remarkably, the presence of Tig considerably slowed the progression to translation elongation and retained IF1 in the resulting 70S initiation complex (70S IC). Molecular modeling of Tetracyclines bound to the 30S pre-IC and 30S IC indicated that the antibiotics binding site topography fluctuates along the initiation pathway. Mainly, 30S complexes show potential contacts between Dem or Tig with IF1, providing a structural rationale for the enhanced affinity of the antibiotics in the presence of the factor. Altogether, our data indicate that Tetracyclines inhibit translation initiation by allosterically perturbing the IF3 layout on the 30S, retaining IF1 during 70S IC formation, and slowing the transition toward translation elongation. Thus, this study describes a new complementary mechanism by which Tetracyclines may inhibit bacterial protein synthesis.

scholarly journals Leucine or carbohydrate supplementation reduces AMPK and eEF2 phosphorylation and extends postprandial muscle protein synthesis in rats

2011 ◽  
Vol 301 (6) ◽  
pp. E1236-E1242 ◽  
Author(s):  
Gabriel J. Wilson ◽  
Donald K. Layman ◽  
Christopher J. Moulton ◽  
Layne E. Norton ◽  
Tracy G. Anthony ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Test Meal ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Adenosine Monophosphate ◽  
Energy Status ◽  
Sprague Dawley ◽  
Translation Elongation ◽  
Cellular Energy ◽  
Mtorc1 Signaling

Muscle protein synthesis (MPS) increases after consumption of a protein-containing meal but returns to baseline values within 3 h despite continued elevations of plasma amino acids and mammalian target of rapamycin (mTORC1) signaling. This study evaluated the potential for supplemental leucine (Leu), carbohydrates (CHO), or both to prolong elevated MPS after a meal. Male Sprague-Dawley rats (∼270 g) trained to consume three meals daily were food deprived for 12 h, and then blood and gastrocnemius muscle were collected 0, 90, or 180 min after a standard 4-g test meal (20% whey protein). At 135 min postmeal, rats were orally administered 2.63 g of CHO, 270 mg of Leu, both, or water (sham control). Following test meal consumption, MPS peaked at 90 min and then returned to basal ( time 0) rates at 180 min, although ribosomal protein S6 kinase and eIF4E-binding protein-1 phosphorylation remained elevated. In contrast, rats administered Leu and/or CHO supplements at 135 min postmeal maintained peak MPS through 180 min. MPS was inversely associated with the phosphorylation states of translation elongation factor 2, the “cellular energy sensor” adenosine monophosphate-activated protein kinase-α (AMPKα) and its substrate acetyl-CoA carboxylase, and increases in the ratio of AMP/ATP. We conclude that the incongruity between MPS and mTORC1 at 180 min reflects a block in translation elongation due to reduced cellular energy. Administering Leu or CHO supplements ∼2 h after a meal maintains cellular energy status and extends the postprandial duration of MPS.

scholarly journals Microbial Metabolites in Colorectal Cancer: Basic and Clinical Implications

Metabolites ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 159
Author(s):  
Yao Peng ◽  
Yuqiang Nie ◽  
Jun Yu ◽  
Chi Chun Wong
Keyword(s):  
Colorectal Cancer ◽  
Gut Microbiota ◽  
Cancer Diagnosis ◽  
Intestinal Tract ◽  
Clinical Applications ◽  
Diagnosis And Treatment ◽  
Clinical Implications ◽  
Microbial Metabolites ◽  
Colorectal Tumorigenesis ◽  
Technology Studies

Colorectal cancer (CRC) is one of the leading cancers that cause cancer-related deaths worldwide. The gut microbiota has been proved to show relevance with colorectal tumorigenesis through microbial metabolites. By decomposing various dietary residues in the intestinal tract, gut microbiota harvest energy and produce a variety of metabolites to affect the host physiology. However, some of these metabolites are oncogenic factors for CRC. With the advent of metabolomics technology, studies profiling microbiota-derived metabolites have greatly accelerated the progress in our understanding of the host-microbiota metabolism interactions in CRC. In this review, we briefly summarize the present metabolomics techniques in microbial metabolites researches and the mechanisms of microbial metabolites in CRC pathogenesis, furthermore, we discuss the potential clinical applications of microbial metabolites in cancer diagnosis and treatment.

P32 Investigating novel mutant mouse models of motor neuron disease

2010 ◽  
Vol 20 ◽  
pp. S13
Author(s):  
P. McGoldrick ◽  
J. Dick ◽  
T. Ricketts ◽  
A. Acevedo-Arozena ◽  
E. Fisher ◽  
...  
Keyword(s):  
Motor Neuron ◽  
Motor Neuron Disease ◽  
Mouse Models ◽  
Mutant Mouse

scholarly journals Mutational landscape of EGFR-, MYC-, and Kras-driven genetically engineered mouse models of lung adenocarcinoma

2016 ◽  
Vol 113 (42) ◽  
pp. E6409-E6417 ◽  
Author(s):  
David G. McFadden ◽  
Katerina Politi ◽  
Arjun Bhutkar ◽  
Frances K. Chen ◽  
Xiaoling Song ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Mouse Models ◽  
Cancer Progression ◽  
Large Scale ◽  
Human Cancer ◽  
Genetically Engineered ◽  
Model Systems ◽  
Driver Mutations ◽  
Genetic Profile ◽  
Genetically Engineered Mouse Models

Genetically engineered mouse models (GEMMs) of cancer are increasingly being used to assess putative driver mutations identified by large-scale sequencing of human cancer genomes. To accurately interpret experiments that introduce additional mutations, an understanding of the somatic genetic profile and evolution of GEMM tumors is necessary. Here, we performed whole-exome sequencing of tumors from three GEMMs of lung adenocarcinoma driven by mutant epidermal growth factor receptor (EGFR), mutant Kirsten rat sarcoma viral oncogene homolog (Kras), or overexpression of MYC proto-oncogene. Tumors from EGFR- and Kras-driven models exhibited, respectively, 0.02 and 0.07 nonsynonymous mutations per megabase, a dramatically lower average mutational frequency than observed in human lung adenocarcinomas. Tumors from models driven by strong cancer drivers (mutant EGFR and Kras) harbored few mutations in known cancer genes, whereas tumors driven by MYC, a weaker initiating oncogene in the murine lung, acquired recurrent clonal oncogenic Kras mutations. In addition, although EGFR- and Kras-driven models both exhibited recurrent whole-chromosome DNA copy number alterations, the specific chromosomes altered by gain or loss were different in each model. These data demonstrate that GEMM tumors exhibit relatively simple somatic genotypes compared with human cancers of a similar type, making these autochthonous model systems useful for additive engineering approaches to assess the potential of novel mutations on tumorigenesis, cancer progression, and drug sensitivity.

Repurposing [11C]MC1 for PET Imaging of Cyclooxygenase-2 in Colorectal Cancer Xenograft Mouse Models

2021 ◽  
Author(s):  
Amanda J. Boyle ◽  
Andrea Narvaez ◽  
Junchao Tong ◽  
Sami S. Zoghbi ◽  
Victor W. Pike ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Mouse Models ◽  
Pet Imaging ◽  
Cyclooxygenase 2

scholarly journals The Oxazolidinone Linezolid Inhibits Initiation of Protein Synthesis in Bacteria

1998 ◽  
Vol 42 (12) ◽  
pp. 3251-3255 ◽  
Author(s):  
Steve M. Swaney ◽  
Hiroyuki Aoki ◽  
M. Clelia Ganoza ◽  
Dean L. Shinabarger
Keyword(s):  
Protein Synthesis ◽  
Complex Formation ◽  
Antimicrobial Agents ◽  
Ribosomal Subunit ◽  
Multidrug Resistant ◽  
Binary Complex ◽  
Initiation Complex ◽  
Ribosomal Subunits ◽  
Bacterial Translation

ABSTRACT The oxazolidinones represent a new class of antimicrobial agents which are active against multidrug-resistant staphylococci, streptococci, and enterococci. Previous studies have demonstrated that oxazolidinones inhibit bacterial translation in vitro at a step preceding elongation but after the charging ofN-formylmethionine to the initiator tRNA molecule. The event that occurs between these two steps is termed initiation. Initiation of protein synthesis requires the simultaneous presence of N-formylmethionine-tRNA, the 30S ribosomal subunit, mRNA, GTP, and the initiation factors IF1, IF2, and IF3. An initiation complex assay measuring the binding of [3H]N-formylmethionyl-tRNA to ribosomes in response to mRNA binding was used in order to investigate the mechanism of oxazolidinone action. Linezolid inhibited initiation complex formation with either the 30S or the 70S ribosomal subunits fromEscherichia coli. In addition, complex formation withStaphylococcus aureus 70S tight-couple ribosomes was inhibited by linezolid. Linezolid did not inhibit the independent binding of either mRNA or N-formylmethionyl-tRNA toE. coli 30S ribosomal subunits, nor did it prevent the formation of the IF2–N-formylmethionyl-tRNA binary complex. The results demonstrate that oxazolidinones inhibit the formation of the initiation complex in bacterial translation systems by preventing formation of theN-formylmethionyl-tRNA–ribosome–mRNA ternary complex.

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