scholarly journals Rapamycin Inhibits Liver Growth during Refeeding in Rats via Control of Ribosomal Protein Translation but Not Cap-Dependent Translation Initiation

2006 ◽  
Vol 136 (1) ◽  
pp. 27-33 ◽  
Author(s):  
Padmanabhan Anand ◽  
Philip A. Gruppuso
Keyword(s):  
Ribosomal Protein ◽  
Translation Initiation ◽  
Protein Translation ◽  
Liver Growth

scholarly journals Inhibition of eEF2K synergizes with glutaminase inhibitors or 4EBP1 depletion to suppress growth of triple-negative breast cancer cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
YoungJun Ju ◽  
Yaacov Ben-David ◽  
Daniela Rotin ◽  
Eldad Zacksenhaus
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Translation Initiation ◽  
Triple Negative ◽  
Elongation Factor ◽  
Protein Translation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Related Factors ◽  
Metabolic Conditions

AbstractThe eukaryotic elongation factor-2 kinase, eEF2K, which restricts protein translation elongation, has been identified as a potential therapeutic target for diverse types of malignancies including triple negative breast cancer (TNBC). However, the contexts in which eEF2K inhibition is essential in TNBC and its consequences on the proteome are largely unknown. Here we show that genetic or pharmacological inhibition of eEF2K cooperated with glutamine (Gln) starvation, and synergized with glutaminase (GLS1) inhibitors to suppress growth of diverse TNBC cell lines. eEF2K inhibition also synergized with depletion of eukaryotic translation initiation factor 4E-binding protein 1 (eIF4EBP1; 4EBP1), a suppressor of eukaryotic protein translation initiation factor 4E (eIF4E), to induce c-MYC and Cyclin D1 expression, yet attenuate growth of TNBC cells. Proteomic analysis revealed that whereas eEF2K depletion alone uniquely induced Cyclin Dependent Kinase 1 (CDK1) and 6 (CDK6), combined depletion of eEF2K and 4EBP1 resulted in overlapping effects on the proteome, with the highest impact on the ‘Collagen containing extracellular matrix’ pathway (e.g. COL1A1), as well as the amino-acid transporter, SLC7A5/LAT1, suggesting a regulatory loop via mTORC1. In addition, combined depletion of eEF2K and 4EBP1 indirectly reduced the levels of IFN-dependent innate immune response-related factors. Thus, eEF2K inhibition triggers cell cycle arrest/death under unfavourable metabolic conditions such as Gln-starvation/GLS1 inhibition or 4EBP1 depletion, uncovering new therapeutic avenues for TNBC and underscoring a pressing need for clinically relevant eEF2K inhibitors.

scholarly journals Structural domains within the HIV-1 mRNA and the ribosomal protein S25 influence cap-independent translation initiation

FEBS Journal ◽  
2016 ◽  
Vol 283 (13) ◽  
pp. 2508-2527 ◽  
Author(s):  
Felipe Carvajal ◽  
Maricarmen Vallejos ◽  
Beth Walters ◽  
Nataly Contreras ◽  
Marla I. Hertz ◽  
...  
Keyword(s):  
Ribosomal Protein ◽  
Translation Initiation ◽  
Structural Domains ◽  
Hiv 1 ◽  
Independent Translation

scholarly journals Universal scanning-free initiation of eukaryote protein translation–a new normal

2021 ◽  
Vol 12 (1) ◽  
pp. 129-131
Author(s):  
Saranya Auparakkitanon ◽  
Prapon Wilairat
Keyword(s):  
Translation Initiation ◽  
Untranslated Region ◽  
Unique Feature ◽  
Protein Translation ◽  
Initiation Codon ◽  
Initiation Complex ◽  
New Normal ◽  
Free Translation

Abstract A unique feature of eukaryote initiation of protein translation is a so-called scanning of 5′-untranslated region (5′-UTR) by a ribosome initiation complex to enable bound Met-tRNAi access to the initiation codon located further downstream. Here, we propose a universal scanning-free translation initiation model that is independent of 5′-UTR length and applicable to both 5′-m7G (capped) and uncapped mRNAs.

scholarly journals Escherichia coli Ribosomal Protein S1 Unfolds Structured mRNAs Onto the Ribosome for Active Translation Initiation

PLoS Biology ◽  
2013 ◽  
Vol 11 (12) ◽  
pp. e1001731 ◽  
Author(s):  
Mélodie Duval ◽  
Alexey Korepanov ◽  
Olivier Fuchsbauer ◽  
Pierre Fechter ◽  
Andrea Haller ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Ribosomal Protein ◽  
Translation Initiation ◽  
Ribosomal Protein S1

Molecular Mechanism of Hepcidin Deficiency in a Patient with Juvenile Hemochromatosis.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3194-3194
Author(s):  
Alexandra Rideau ◽  
Bastien Mangeat ◽  
Thomas Matthes ◽  
Didier Trono ◽  
Photis Beris
Keyword(s):  
Translation Initiation ◽  
Consensus Sequence ◽  
Protein Translation ◽  
Translation Initiation Site ◽  
Wild Type ◽  
Gfp Expression ◽  
Translational Initiation ◽  
Coding Sequence ◽  
Mammalian Expression ◽  
Juvenile Hemochromatosis

Abstract In eukaryotes protein translation is initiated at an AUG codon typically located within a so-called Kozak sequence (GCCRCC AUG G), a motif that presumably promotes the correct positioning of the mRNA in the ribosome. Recently, we described a patient suffering from juvenile hemochromatosis resulting from a lack of hepcidin production (Blood;15 June 2004; Epub ahead of print). We further revealed that this defect coincided with a G-to-A point mutation at position +14 of the 5′untranslated region (5′UTR) of the HAMP gene. This nucleotide change led to the creation of an ATG codon, out of frame with the physiological pre-hepcidin initiator located at positions +39-41. We speculated that this new ATG, which was embedded within a Kozak consensus sequence, acted as an aberrant translation initiation site that precluded hepcidin synthesis. In order to verify this hypothesis, we cloned in a mammalian expression vector the wild-type and mutant HAMP 5′UTR upstream of a modified EGFP cDNA, replacing the EGFP ATG by the HAMP physiological initiation codon. The resulting vectors were transfected into 293T cells. Presence of the additional ATG in the HAMP 5′UTR led to a 93 % decrease in GFP expression compared with wild-type. To confirm that this effect resulted from aberrant translation initiation at this site, a one-nucleotide deletion was introduced at the very 5′ end of the EGFP coding sequence, in order to place it in frame with the mutant HAMP 5′UTR proximal ATG (GTG in the wild-type sequence). This restored GFP expression to levels obtained when its coding sequence was in frame with the physiological hepcidin ATG of a wild-type HAMP 5′UTR. Our results very strongly suggest that the G to A mutation at position +14 of the HAMP gene 5′UTR blocks hepcidin production by inducing aberrant translational initiation of the pre-hepcidin mRNA. Whether a stable protein is synthesized from the mutated HAMP mRNA, which does not contain a stop codon in frame with the +14 AUG, remains to be determined. It is however unlikely that such protein contributes to the pathology observed in our patient, since the two other cases of hepcidin deficiency reported so far exhibit the same phenotype as our patient in spite of harbouring different mutations in the HAMP gene.

The Translation Initiation Factor eIF4E Is Overexpressed in Multiple Myeloma and Is Critical for Myeloma Cell Proliferation and Survival

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1853-1853 ◽  
Author(s):  
Shirong Li ◽  
MeiHua Jin ◽  
Ailing Liu ◽  
Markus Y. Mapara ◽  
Suzanne Lentzsch
Keyword(s):  
Multiple Myeloma ◽  
Protein Synthesis ◽  
Translation Initiation ◽  
Clinical Care ◽  
Protein Translation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Mrna Levels ◽  
Myeloma Cells ◽  
Rpmi 8226

Abstract Abstract 1853 Methods: The translation initiation factor eIF4E is central to protein synthesis in general, and overexpression and/or activation of eIF4E is associated with a malignant phenotype by regulating oncogenic protein translation. Several previous publications indicate that aberrant control of protein synthesis contributes to lymphoma genesis but the exact role of protein translation in multiple myeloma (MM) is less clear. Therefore, understanding the mechanisms that control protein synthesis is an emerging new research area in MM with significant potential for developing innovative therapies. The goal of this study was to determine the role and regulation of eIF4E, as well as the effects of protein translation controlling drugs in MM. Results: By western blot analysis as well as RT-PCR we found that eIF4E protein and mRNA levels are significantly elevated (up to 20 fold) in MM cell lines (H929, RPMI-8226, MM.1S and OPM2) and primary myeloma cells compared to normal plasma cells. Silencing of eIF4E gene expression in RPMI-8226 MM cells by a stable and inducible shRNA system significantly decreased viability of myeloma cells (by ∼ 43%) but not of HEK 293 suggesting a higher dependency of MM cells to protein translation. Next we evaluated different drugs including pomalidomide, rapamycin, pp242, 4EGI-1 and ribavirin, that are known to inhibit protein synthesis for their effects on protein translation in MM. By m7GTP pull down assays we evaluated the effects of the different drugs on eIF4E expression and activity. Rapamycin blocked the phosphorylation of 4EBP1 and eIF4E release, and subsequently inhibited eIF4G binding. The compound 4EGI-1 decreased the interaction between eIF4E and eIF4G. Pomalidomide decreased eIF4E protein expression. All drugs inhibited MM cell DNA synthesis measured by 3H-Thymidine incorporation. Treatment with pomalidomide (10uM), rapamycin (40nM), pp242 (10uM), 4EGI1 (50uM) or ribavirin (50uM) for 48h significantly decreased (p<0.05) proliferation by 43–62% indicating that drugs controlling protein translation inhibit MM growth. We also found that all drugs decreased expression of eIF4E dependent targets such as cyclin D1 and c-myc. Conclusion: Here we show that eIF4E, a key player in translational control, is highly expressed in MM cells and critical for MM growth and survival. Therefore our study helps to understand the function and regulatory mechanism of eIF4E in MM. Further the evaluation of drugs targeting protein translation provides the basis for the optimization of current MM treatment or to open up new strategies such as targeting protein translation in future MM therapy. Disclosures: Lentzsch: Celgene Corp: Consultancy, Research Funding; Onyx: Consultancy; Genzyme: Consultancy; prIME Oncology: Honoraria; Imedex: Honoraria; Clinical Care Options: Honoraria.

Sign in / Sign up

Export Citation Format

Share Document