scholarly journals Cytoskeletal vimentin regulates cell size and autophagy through mTORC1 signaling

2021 ◽  
Author(s):  
John Elias Eriksson ◽  
Ponnuswamy Mohanasundaram ◽  
Leila S Coelho-Rato ◽  
Mayank Modi ◽  
Marta Urbanska ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Cell Size ◽  
Cancer Progression ◽  
Ribosome Biogenesis ◽  
Mrna Translation ◽  
Autophagic Flux ◽  
Intermediate Filament Protein ◽  
Downstream Target ◽  
Mtorc1 Signaling ◽  
Filament Protein

The nutrient-activated mTORC1 (mechanistic target of rapamycin kinase complex 1) signaling pathway determines cell size by controlling mRNA translation, ribosome biogenesis, protein synthesis, and autophagy. Here we show that vimentin, a cytoskeletal intermediate filament protein that we know to be important for wound healing and cancer progression, determines cell size through mTORC1 signaling, an effect that is also manifested at the organism level in mice. We found that vimentin maintains normal cell size by supporting mTORC1 activation and through inhibition of autophagic flux. This regulation is manifested at all levels of downstream target activation and regulation of protein synthesis. We show that vimentin controls mTORC1 mobility by allowing access to lysosomes. Vimentin inhibits the autophagic flux in normal fibroblasts even under starved conditions, indicating a growth factor-independent inhibition of autophagy at the level of mTORC1. Our findings demonstrate that vimentin couples cell size signaling and autophagy with the biomechanics, sensing, and kinetic functions of the cytoskeleton.

scholarly journals c-Myc overexpression increases ribosome biogenesis and protein synthesis independent of mTORC1 activation in mouse skeletal muscle

2021 ◽  
Author(s):  
Takahiro Mori ◽  
Satoru Ato ◽  
Jonas R. Knudsen ◽  
Carlos Henriquez-Olguin ◽  
Zhencheng Li ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Skeletal Muscles ◽  
Ribosome Biogenesis ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Mrna Translation ◽  
Adeno Associated Virus ◽  
Mtorc1 Signaling ◽  
Mtorc1 Activation

High-intensity muscle contractions (HiMC) are known to increase c-Myc expression which is known to stimulate ribosome biogenesis and protein synthesis in most cells. However, while c-Myc mRNA transcription and c-Myc mRNA translation have been shown to be upregulated following resistance exercise concomitantly with increased ribosome biogenesis, this has not been tested directly. We investigated the effect of adeno-associated virus (AAV)-mediated c-Myc overexpression, with or without fasting or percutaneous electrical stimulation-induced HiMC, on ribosome biogenesis and protein synthesis in adult mouse skeletal muscles. AAV-mediated overexpression of c-Myc in mouse skeletal muscles for 2 weeks increased the DNA polymerase subunit POL1 mRNA, 45S-pre-rRNA, total RNA, and muscle protein synthesis without altering mechanistic target of rapamycin complex 1 (mTORC1) signaling under both ad libitum and fasted conditions. RNA-seq analyses revealed that c-Myc overexpression mainly regulated ribosome biogenesis-related biological processes. The protein synthesis response to c-Myc overexpression mirrored the response with HiMC. No additional effect of combining c-Myc overexpression and HiMC was observed. Our results suggest that c-Myc overexpression is sufficient to stimulate skeletal muscle ribosome biogenesis and protein synthesis without activation of mTORC1. Therefore, the HiMC-induced increase in c-Myc may contribute to ribosome biogenesis and increased protein synthesis following HiMC.

Intermediate filament protein synthesis in preimplantation murine embryos

1983 ◽  
Vol 99 (2) ◽  
pp. 447-455 ◽  
Author(s):  
Robert G. Oshima ◽  
William E. Howe ◽  
F.George Klier ◽  
Eileen D. Adamson ◽  
Lynne H. Shevinsky
Keyword(s):  
Protein Synthesis ◽  
Intermediate Filament ◽  
Intermediate Filament Protein ◽  
Murine Embryos ◽  
Filament Protein

scholarly journals Adenosine kinase regulation of cardiomyocyte hypertrophy

2011 ◽  
Vol 300 (5) ◽  
pp. H1722-H1732 ◽  
Author(s):  
John T. Fassett ◽  
Xinli Hu ◽  
Xin Xu ◽  
Zhongbing Lu ◽  
Ping Zhang ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Cell Size ◽  
Adenosine Receptors ◽  
Adenosine Kinase ◽  
Dominant Negative ◽  
Neonatal Rat ◽  
Cardiomyocyte Hypertrophy ◽  
Rat Cardiomyocytes ◽  
Mtorc1 Signaling ◽  
Constitutively Active

There is evidence that extracellular adenosine can attenuate cardiac hypertrophy, but the mechanism by which this occurs is not clear. Here we investigated the role of adenosine receptors and adenosine metabolism in attenuation of cardiomyocyte hypertrophy. Phenylephrine (PE) caused hypertrophy of neonatal rat cardiomyocytes with increases of cell surface area, protein synthesis, and atrial natriuretic peptide (ANP) expression. These responses were attenuated by 5 μM 2-chloroadenosine (CADO; adenosine deaminase resistant adenosine analog) or 10 μM adenosine. While antagonism of adenosine receptors partially blocked the reduction of ANP expression produced by CADO, it did not restore cell size or protein synthesis. In support of a role for intracellular adenosine metabolism in regulating hypertrophy, the adenosine kinase (AK) inhibitors iodotubercidin and ABT-702 completely reversed the attenuation of cell size, protein synthesis, and expression of ANP by CADO or ADO. Examination of PE-induced phosphosignaling pathways revealed that CADO treatment did not reduce AKTSer473 phosphorylation but did attenuate sustained phosphorylation of RafSer338 (24–48 h), mTORSer2448 (24–48 h), p70S6kThr389 (2.5–48 h), and ERKThr202/Tyr204 (48 h). Inhibition of AK restored activation of these enzymes in the presence of CADO. Using dominant negative and constitutively active Raf adenoviruses, we found that Raf activation is necessary and sufficient for PE-induced mTORC1 signaling and cardiomyocyte hypertrophy. CADO treatment still blocked p70S6kThr389 phosphorylation and hypertrophy downstream of constitutively active Raf, however, despite a high level phosphorylation of ERKThr202/Tyr204 and AKTSer473. Reduction of Raf-induced p70S6kThr389 phosphorylation and hypertrophy by CADO was reversed by inhibiting AK. Together, these results identify AK as an important mediator of adenosine attenuation of cardiomyocyte hypertrophy, which acts, at least in part, through inhibition of Raf signaling to mTOR/p70S6k.

scholarly journals Translation Stress Regulates Ribosome Synthesis and Cell Proliferation

2018 ◽  
Vol 19 (12) ◽  
pp. 3757 ◽  
Author(s):  
Sivakumar Vadivel Gnanasundram ◽  
Robin Fåhraeus
Keyword(s):  
Protein Synthesis ◽  
Ribosome Biogenesis ◽  
Developmental Disorders ◽  
Mrna Translation ◽  
Cellular Growth ◽  
Pol I ◽  
Global Protein Synthesis ◽  
Sense And Respond ◽  
Pol Iii ◽  
Factor C

Ribosome and protein synthesis are major metabolic events that control cellular growth and proliferation. Impairment in ribosome biogenesis pathways and mRNA translation is associated with pathologies such as cancer and developmental disorders. Processes that control global protein synthesis are tightly regulated at different levels by numerous factors and linked with multiple cellular signaling pathways. Several of these merge on the growth promoting factor c-Myc, which induces ribosome biogenesis by stimulating Pol I, Pol II, and Pol III transcription. However, how cells sense and respond to mRNA translation stress is not well understood. It was more recently shown that mRNA translation stress activates c-Myc, through a specific induction of E2F1 synthesis via a PI3Kδ-dependent pathway. This review focuses on how this novel feedback pathway stimulates cellular growth and proliferation pathways to synchronize protein synthesis with ribosome biogenesis. It also describes for the first time the oncogenic activity of the mRNA, and not the encoded protein.

scholarly journals Ribosome Biogenesis Alterations in Colorectal Cancer

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2361
Author(s):  
Sophie Nait Slimane ◽  
Virginie Marcel ◽  
Tanguy Fenouil ◽  
Frédéric Catez ◽  
Jean-Christophe Saurin ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Protein Synthesis ◽  
Cell Growth ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Ribosome Biogenesis ◽  
Predictive Biomarkers ◽  
Cancer Cell Growth ◽  
Therapeutic Drugs ◽  
Key Driver

Many studies have focused on understanding the regulation and functions of aberrant protein synthesis in colorectal cancer (CRC), leaving the ribosome, its main effector, relatively underappreciated in CRC. The production of functional ribosomes is initiated in the nucleolus, requires coordinated ribosomal RNA (rRNA) processing and ribosomal protein (RP) assembly, and is frequently hyperactivated to support the needs in protein synthesis essential to withstand unremitting cancer cell growth. This elevated ribosome production in cancer cells includes a strong alteration of ribosome biogenesis homeostasis that represents one of the hallmarks of cancer cells. None of the ribosome production steps escape this cancer-specific dysregulation. This review summarizes the early and late steps of ribosome biogenesis dysregulations described in CRC cell lines, intestinal organoids, CRC stem cells and mouse models, and their possible clinical implications. We highlight how this cancer-related ribosome biogenesis, both at quantitative and qualitative levels, can lead to the synthesis of ribosomes favoring the translation of mRNAs encoding hyperproliferative and survival factors. We also discuss whether cancer-related ribosome biogenesis is a mere consequence of cancer progression or is a causal factor in CRC, and how altered ribosome biogenesis pathways can represent effective targets to kill CRC cells. The association between exacerbated CRC cell growth and alteration of specific steps of ribosome biogenesis is highlighted as a key driver of tumorigenesis, providing promising perspectives for the implementation of predictive biomarkers and the development of new therapeutic drugs.

Subcellular localization of an intermediate filament protein and its mRNA in glial cells

1989 ◽  
Vol 9 (10) ◽  
pp. 4556-4559
Author(s):  
P V Sarthy ◽  
M Fu ◽  
J Huang
Keyword(s):  
Glial Cell ◽  
Intermediate Filament ◽  
Mrna Translation ◽  
Mrna Localization ◽  
Intermediate Filament Protein ◽  
Cell Cytoplasm ◽  
Distal Process ◽  
Spatially Distributed ◽  
Actin Mrna ◽  
Filament Protein

Eucaryotic mRNAs are generally localized in the cell body, where most protein synthesis occurs. We have found that mRNAs encoding the glial intermediate filament protein are spatially distributed in the glial cell cytoplasm close to the location of the glial filaments. Whereas the glial filament protein mRNA was located predominantly in the distal process, actin mRNA was found almost exclusively in the apical portion of the glial cell. This pattern of mRNA localization might provide a mechanism for synthesis of proteins in specific subcellular compartments by mRNA translation locally.

scholarly journals Role of Eukaryotic Initiation Factors during Cellular Stress and Cancer Progression

2016 ◽  
Vol 2016 ◽  
pp. 1-19 ◽  
Author(s):  
Divya Khandige Sharma ◽  
Kamiko Bressler ◽  
Harshil Patel ◽  
Nirujah Balasingam ◽  
Nehal Thakor
Keyword(s):  
Protein Synthesis ◽  
Cancer Progression ◽  
Translation Initiation ◽  
Tumor Development ◽  
Mrna Translation ◽  
Translation Control ◽  
Initiation Factors ◽  
Eukaryotic Initiation Factors ◽  
Rate Limiting Step ◽  
Precise Understanding

Protein synthesis can be segmented into distinct phases comprising mRNA translation initiation, elongation, and termination. Translation initiation is a highly regulated and rate-limiting step of protein synthesis that requires more than 12 eukaryotic initiation factors (eIFs). Extensive evidence shows that the transcriptome and corresponding proteome do not invariably correlate with each other in a variety of contexts. In particular, translation of mRNAs specific to angiogenesis, tumor development, and apoptosis is altered during physiological and pathophysiological stress conditions. In cancer cells, the expression and functions of eIFs are hampered, resulting in the inhibition of global translation and enhancement of translation of subsets of mRNAs by alternative mechanisms. A precise understanding of mechanisms involving eukaryotic initiation factors leading to differential protein expression can help us to design better strategies to diagnose and treat cancer. The high spatial and temporal resolution of translation control can have an immediate effect on the microenvironment of the cell in comparison with changes in transcription. The dysregulation of mRNA translation mechanisms is increasingly being exploited as a target to treat cancer. In this review, we will focus on this context by describing both canonical and noncanonical roles of eIFs, which alter mRNA translation.

scholarly journals TOP mRNPs: Molecular Mechanisms and Principles of Regulation

Biomolecules ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. 969 ◽  
Author(s):  
Eric Cockman ◽  
Paul Anderson ◽  
Pavel Ivanov
Keyword(s):  
Protein Synthesis ◽  
Translational Control ◽  
Gene Networks ◽  
Cellular Response ◽  
Ribosome Biogenesis ◽  
Molecular Mechanisms ◽  
Mrna Translation ◽  
Ribonucleoprotein Complexes ◽  
Global Protein Synthesis ◽  
Protein Components

The cellular response to changes in the surrounding environment and to stress requires the coregulation of gene networks aiming to conserve energy and resources. This is often achieved by downregulating protein synthesis. The 5’ Terminal OligoPyrimidine (5’ TOP) motif-containing mRNAs, which encode proteins that are essential for protein synthesis, are the primary targets of translational control under stress. The TOP motif is a cis-regulatory RNA element that begins directly after the m7G cap structure and contains the hallmark invariant 5’-cytidine followed by an uninterrupted tract of 4–15 pyrimidines. Regulation of translation via the TOP motif coordinates global protein synthesis with simultaneous co-expression of the protein components required for ribosome biogenesis. In this review, we discuss architecture of TOP mRNA-containing ribonucleoprotein complexes, the principles of their assembly, and the modes of regulation of TOP mRNA translation.

scholarly journals Regulation of protein synthesis associated with skeletal muscle hypertrophy by insulin-, amino acid- and exercise-induced signalling

2004 ◽  
Vol 63 (2) ◽  
pp. 351-356 ◽  
Author(s):  
Douglas R. Bolster ◽  
Leonard S. Jefferson ◽  
Scot R. Kimball
Keyword(s):  
Skeletal Muscle ◽  
Signal Transduction ◽  
Amino Acids ◽  
Protein Synthesis ◽  
Ribosome Biogenesis ◽  
Muscle Hypertrophy ◽  
Current Knowledge ◽  
Signal Transduction Pathway ◽  
Mrna Translation ◽  
Transduction Pathway

Although insulin, amino acids and exercise individually activate multiple signal transduction pathways in skeletal muscle, one pathway, the phosphatidylinositol 3-kinase (PI3K)–mammalian target of rapamycin (mTOR) signalling pathway, is a target of all three. Activation of the PI3K–mTOR signal transduction pathway results in both acute (i.e. occurring in minutes to hours) and long-term (i.e. occurring in hours to days) up-regulation of protein synthesis through modulation of multiple steps involved in mediating the initiation of mRNA translation and ribosome biogenesis respectively. In addition, changes in gene expression through altered patterns of mRNA translation promote cell growth, which in turn promotes muscle hypertrophy. The focus of the present discussion is to review current knowledge concerning the mechanism(s) through which insulin, amino acids and resistance exercise act to activate the PI3K–mTOR signal transduction pathway and thereby enhance the rate of protein synthesis in muscle.

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