scholarly journals TGFβ/Activin signalling is required for ribosome biogenesis and cell growth in Drosophila salivary glands

Open Biology ◽  
2017 ◽  
Vol 7 (1) ◽  
pp. 160258 ◽  
Author(s):  
Torcato Martins ◽  
Nadia Eusebio ◽  
Andreia Correia ◽  
Joana Marinho ◽  
Fernando Casares ◽  
...  
Keyword(s):  
Cell Growth ◽  
Salivary Glands ◽  
Ribosomal Proteins ◽  
Ribosome Biogenesis ◽  
Growth Control ◽  
Tissue Growth ◽  
Cellular Growth ◽  
Nucleolar Structure ◽  
Cell Growth And Proliferation ◽  
Tgfβ Superfamily

Signalling by TGFβ superfamily factors plays an important role in tissue growth and cell proliferation. In Drosophila , the activity of the TGFβ/Activin signalling branch has been linked to the regulation of cell growth and proliferation, but the cellular and molecular basis for these functions are not fully understood. In this study, we show that both the RII receptor Punt (Put) and the R-Smad Smad2 are strongly required for cell and tissue growth. Knocking down the expression of Put or Smad2 in salivary glands causes alterations in nucleolar structure and functions. Cells with decreased TGFβ/Activin signalling accumulate intermediate pre-rRNA transcripts containing internal transcribed spacer 1 regions accompanied by the nucleolar retention of ribosomal proteins. Thus, our results show that TGFβ/Activin signalling is required for ribosomal biogenesis, a key aspect of cellular growth control. Importantly, overexpression of Put enhanced cell growth induced by Drosophila Myc, a well-characterized inducer of nucleolar hypertrophy and ribosome biogenesis.

scholarly journals Control of ribosomal protein synthesis by Microprocessor complex

2020 ◽  
Author(s):  
Xuan Jiang ◽  
Amit Prabhakar ◽  
Stephanie M. Van der Voorn ◽  
Prajakta Ghatpande ◽  
Barbara Celona ◽  
...  
Keyword(s):  
Cell Growth ◽  
Nuclear Export ◽  
Ribosomal Proteins ◽  
Ribosome Biogenesis ◽  
Cellular Growth ◽  
New Paradigm ◽  
Erythroid Progenitors ◽  
Conditional Deletion ◽  
Microprocessor Complex ◽  
Ribosomal Protein Synthesis

AbstractRibosome biogenesis in eukaryotes requires stoichiometric production and assembly of 80 ribosomal proteins (RPs) and 4 ribosomal RNAs, and its rate must be coordinated with cellular growth. The indispensable regulator of RP biosynthesis is the 5’-terminal oligopyrimidine (TOP) motif, spanning the transcription start site of all RP genes. Here we show that the Microprocessor complex, previously linked to the first step of processing microRNAs (miRNAs), coregulates RP expression by binding the TOP motif of nascent RP mRNAs and stimulating transcription elongation via resolution of DNA/RNA hybrids. Cell growth arrest triggers nuclear export and degradation of the Microprocessor protein Drosha by the E3 ubiquitin ligase Nedd4, accumulation of DNA/RNA hybrids at RP gene loci, decreased RP synthesis, and ribosome deficiency, hence synchronizing ribosome production with cell growth. Conditional deletion of Drosha in erythroid progenitors phenocopies human ribosomopathies, in which ribosomal insufficiency leads to anemia. Outlining a miRNA-independent role of the Microprocessor complex at the interphase between cell growth and ribosome biogenesis offers a new paradigm by which cells alter their protein biosynthetic capacity and cellular metabolism.

scholarly journals Drosophila TIF-IA is required for ribosome synthesis and cell growth and is regulated by the TOR pathway

2007 ◽  
Vol 179 (6) ◽  
pp. 1105-1113 ◽  
Author(s):  
Savraj S. Grewal ◽  
Justin R. Evans ◽  
Bruce A. Edgar
Keyword(s):  
Cell Growth ◽  
Transcription Initiation ◽  
Ribosomal Proteins ◽  
Ribosome Biogenesis ◽  
Cellular Growth ◽  
Initiation Factor ◽  
Rrna Synthesis ◽  
Messenger Rnas ◽  
Tor Pathway

Synthesis of ribosomal RNA (rRNA) is a key step in ribosome biogenesis and is essential for cell growth. Few studies, however, have investigated rRNA synthesis regulation in vivo in multicellular organisms. Here, we present a genetic analysis of transcription initiation factor IA (TIF-IA), a conserved RNA polymerase I transcription factor. Drosophila melanogaster Tif-IA−/− mutants have reduced levels of rRNA synthesis and sustain a developmental arrest caused by a block in cellular growth. We find that the target of rapamycin (TOR) pathway regulates TIF-IA recruitment to rDNA. Furthermore, we show that the TOR pathway regulates rRNA synthesis in vivo and that TIF-IA overexpression can maintain rRNA transcription when TOR activity is reduced in developing larvae. We propose that TIF-IA acts in vivo as a downstream growth–regulatory target of the TOR pathway. Overexpression of TIF-IA also elevates levels of both 5S RNA and messenger RNAs encoding ribosomal proteins. Stimulation of rRNA synthesis by TIF-IA may therefore provide a feed-forward mechanism to coregulate the levels of other ribosome components.

Controlling cell growth and survival through regulated nutrient transporter expression

2007 ◽  
Vol 406 (1) ◽  
pp. 1-12 ◽  
Author(s):  
Aimee L. Edinger
Keyword(s):  
Cell Growth ◽  
Mammalian Cells ◽  
Growth Control ◽  
Cellular Growth ◽  
Growth And Survival ◽  
Tumour Suppression ◽  
Nutrient Transporter ◽  
Phosphoinositide 3 Kinase ◽  
Cell Growth And Proliferation ◽  
Transporter Expression

Although all cells depend upon nutrients they acquire from the extracellular space, surprisingly little is known about how nutrient uptake is regulated in mammalian cells. Most nutrients are brought into cells by means of specific transporter proteins. In yeast, the expression and trafficking of a wide variety of nutrient transporters is controlled by the TOR (target of rapamycin) kinase. Consistent with this, recent studies in mammalian cells have shown that mTOR (mammalian TOR) and the related protein, PI3K (phosphoinositide 3-kinase), play central roles in coupling nutrient transporter expression to the availability of extrinsic trophic and survival signals. In the case of lymphocytes, it has been particularly well established that these extrinsic signals stimulate cell growth and proliferation in part by regulating nutrient transporter expression. The ability of growth factors to control nutrient access may also play an important role in tumour suppression: the non-homoeostatic growth of tumour cells requires that nutrient transporter expression is uncoupled from trophic factor availability. Also supporting a link between nutrient transporter expression levels and oncogenesis, several recent studies demonstrate that nutrient transporter expression drives, rather than simply parallels, cellular metabolism. This review summarizes the evidence that regulated nutrient transporter expression plays a central role in cellular growth control and highlights the implications of these findings for human disease.

scholarly journals The DHX33 RNA Helicase Promotes mRNA Translation Initiation

2015 ◽  
Vol 35 (17) ◽  
pp. 2918-2931 ◽  
Author(s):  
Yandong Zhang ◽  
Jin You ◽  
Xingshun Wang ◽  
Jason Weber
Keyword(s):  
Translation Initiation ◽  
Ribosomal Proteins ◽  
Ribosome Biogenesis ◽  
Mrna Translation ◽  
Rna Helicase ◽  
Rna Helicases ◽  
80S Ribosome ◽  
Protein Levels ◽  
Cell Growth And Proliferation ◽  
Rna Complexes

DEAD/DEAH box RNA helicases play essential roles in numerous RNA metabolic processes, such as mRNA translation, pre-mRNA splicing, ribosome biogenesis, and double-stranded RNA sensing. Herein we show that a recently characterized DEAD/DEAH box RNA helicase, DHX33, promotes mRNA translation initiation. We isolated intact DHX33 protein/RNA complexes in cells and identified several ribosomal proteins, translation factors, and mRNAs. Reduction of DHX33 protein levels markedly reduced polyribosome formation and caused the global inhibition of mRNA translation that was rescued with wild-type DHX33 but not helicase-defective DHX33. Moreover, we observed an accumulation of mRNA complexes with the 80S ribosome in the absence of functional DHX33, consistent with a stalling in initiation, and DHX33 more preferentially promoted structured mRNA translation. We conclude that DHX33 functions to promote elongation-competent 80S ribosome assembly at the late stage of mRNA translation initiation. Our results reveal a newly recognized function of DHX33 in mRNA translation initiation, further solidifying its central role in promoting cell growth and proliferation.

scholarly journals A Drosophila RNA helicase gene, pitchoune, is required for cell growth and proliferation and is a potential target of d-Myc

Development ◽  
1998 ◽  
Vol 125 (18) ◽  
pp. 3571-3584 ◽  
Author(s):  
S. Zaffran ◽  
A. Chartier ◽  
P. Gallant ◽  
M. Astier ◽  
N. Arquier ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Growth ◽  
Ribosome Biogenesis ◽  
Protein Biosynthesis ◽  
Ectopic Expression ◽  
Rna Helicase ◽  
Potential Target ◽  
Dead Box ◽  
First Instar ◽  
Cell Growth And Proliferation

This article describes the characterization of a new Drosophila gene that we have called pitchoune (pit) (meaning small in Provence) because mutations in this gene produce larvae that cannot grow beyond the first instar larval stage although they can live as long as 7–10 days. All the tissues are equally affected and the perfectly shaped larvae are indistinguishable from first instar wild-type animals. Analysis of mutant somatic clones suggests a function in cell growth and proliferation, which is supported by the fact that cell proliferation is promoted by pit overexpression. Tagged-Pit, when transfected in S2 cells, localizes mainly to the nucleolus, pointing towards a possible role in ribosome biogenesis and, consequently, in protein biosynthesis. pit encodes a DEAD-box RNA helicase, a family of proteins involved in the control of RNA structure in many cellular processes and its closest homologue is a human DEAD-box RNA helicase, MrDb, whose corresponding gene transcription is directly activated by Myc-Max heterodimers (Grandori, C., Mac, J., Siebelt, F., Ayer, D. E. and Eisenman, R. N. (1996) EMBO J. 15, 4344–4357). The patterns of expression of d-myc and pit are superimposable. Ectopic expression of myc in the nervous system drives an ectopic expression of pit in this tissue indicating that in Drosophila as well, pit is a potential target of d-Myc. These results suggest that myc might promote cell proliferation by activating genes that are required in protein biosynthesis, thus linking cell growth and cell proliferation.

scholarly journals The Correlation Between Cell and Nucleus Size is Explained by an Eukaryotic Cell Growth Model

2021 ◽  
Author(s):  
Yufei Wu ◽  
Paul Janmey ◽  
Sean X. Sun
Keyword(s):  
Growth Rate ◽  
Cell Growth ◽  
Cell Volume ◽  
Ribosomal Proteins ◽  
Ribosome Biogenesis ◽  
Eukaryotic Cell ◽  
Nuclear Volume ◽  
Strongly Correlated ◽  
Cell Growth Rate ◽  
A Cell

In eukaryotes, the cell volume is observed to be strongly correlated with the nuclear volume. The slope of this correlation depends on the cell type, growth condition, and the physical environment of the cell. We develop a computational model of cell growth and proteome increase, incorporating the kinetics of amino acid import, protein/ribosome synthesis and degradation, and active transport of proteins between the cytoplasm and the nucleoplasm. We also include a simple model of ribosome biogenesis and assembly. Results show that the cell volume is tightly correlated with the nuclear volume, and the cytoplasm-nucleoplasm transport rates strongly influences the cell growth rate as well as the cytoplasm/nucleoplasm ratio. Ribosome assembly and the ratio of ribosomal proteins to mature ribosomes also influence the cell volume and the cell growth rate. We find that in order to regulate the cell growth rate and the cytoplasm/nucleoplasm ratio, the cell must optimally control groups of kinetic parameters together, which could explain the quantitative roles of canonical growth pathways. Finally, using an extension of our model and single cell RNAseq data, it is possible to construct a detailed proteome distribution, provided that a cell division mechanism is known.

scholarly journals Exploiting cancer vulnerabilities: mTOR, autophagy, and homeostatic imbalance

2017 ◽  
Vol 61 (6) ◽  
pp. 699-710 ◽  
Author(s):  
Charlotte E. Johnson ◽  
Andrew R. Tee
Keyword(s):  
Cell Growth ◽  
Cancer Cells ◽  
Energy Homeostasis ◽  
Cellular Stress ◽  
Growth Control ◽  
Potential Therapeutic Target ◽  
Wide Range ◽  
Cell Growth And Proliferation ◽  
Mtor Complex 1 ◽  
Cell Growth Control

Mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) at lysosomes plays a pivotal role in cell growth control where an array of large multiprotein complexes relay nutrient, energy, and growth signal inputs through mTORC1. In cancer cells, such regulation often becomes disconnected, leading to uncontrolled cell growth and an elevation in cellular stress. Consequently, cancer cells often lose homeostatic balance as they grow in unfavorable conditions, i.e. when nutrients and energy are limited yet mTORC1 is still aberrantly activated. Cancer cells lose signaling flexibility because of hyperactive mTORC1 that leads to heightened cellular stress and loss of nutrient and energy homeostasis, all of which are potential avenues for cancer therapy. Cancer cells often enhance mTORC1 to drive cell growth and proliferation, while also maintaining their survival. Autophagy regulation by mTORC1 is critically involved in nutrient and energy homeostasis, cell growth control, and survival. Studying mTORC1 and autophagy as a potential therapeutic target for cancer treatment has been the focus of a wide range of research over the past few decades. This review will explore the signaling pathways central to mTORC1 and autophagy regulation, and cancer vulnerabilities while considering anticancer therapies.

scholarly journals Ribosome Biogenesis and Cancer: Overview on Ribosomal Proteins

2021 ◽  
Vol 22 (11) ◽  
pp. 5496
Author(s):  
Annalisa Pecoraro ◽  
Martina Pagano ◽  
Giulia Russo ◽  
Annapina Russo
Keyword(s):  
Ribosomal Rna ◽  
Ribosomal Proteins ◽  
Ribosome Biogenesis ◽  
Protein Biosynthesis ◽  
Cellular Respiration ◽  
Mitochondrial Ribosomes ◽  
Ribonucleoprotein Complexes ◽  
Mitochondrial Ribosome ◽  
Energy Consuming ◽  
Cell Growth And Proliferation

Cytosolic ribosomes (cytoribosomes) are macromolecular ribonucleoprotein complexes that are assembled from ribosomal RNA and ribosomal proteins, which are essential for protein biosynthesis. Mitochondrial ribosomes (mitoribosomes) perform translation of the proteins essential for the oxidative phosphorylation system. The biogenesis of cytoribosomes and mitoribosomes includes ribosomal RNA processing, modification and binding to ribosomal proteins and is assisted by numerous biogenesis factors. This is a major energy-consuming process in the cell and, therefore, is highly coordinated and sensitive to several cellular stressors. In mitochondria, the regulation of mitoribosome biogenesis is essential for cellular respiration, a process linked to cell growth and proliferation. This review briefly overviews the key stages of cytosolic and mitochondrial ribosome biogenesis; summarizes the main steps of ribosome biogenesis alterations occurring during tumorigenesis, highlighting the changes in the expression level of cytosolic ribosomal proteins (CRPs) and mitochondrial ribosomal proteins (MRPs) in different types of tumors; focuses on the currently available information regarding the extra-ribosomal functions of CRPs and MRPs correlated to cancer; and discusses the role of CRPs and MRPs as biomarkers and/or molecular targets in cancer treatment.

scholarly journals The roles of ribosomal proteins in nasopharyngeal cancer: culprits, sentinels or both

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Edmund Ui-Hang Sim ◽  
Choon-Weng Lee ◽  
Kumaran Narayanan
Keyword(s):  
Ribosomal Proteins ◽  
Ribosome Biogenesis ◽  
Protein Biosynthesis ◽  
Physiological Activity ◽  
Nasopharyngeal Cancer ◽  
Protein Translation ◽  
Cellular Protein ◽  
Cellular Growth ◽  
Ribosomal Protein Genes ◽  
Relationship Of

AbstractRibosomal protein genes encode products that are essential for cellular protein biosynthesis and are major components of ribosomes. Canonically, they are involved in the complex system of ribosome biogenesis pivotal to the catalysis of protein translation. Amid this tightly organised process, some ribosomal proteins have unique spatial and temporal physiological activity giving rise to their extra-ribosomal functions. Many of these extra-ribosomal roles pertain to cellular growth and differentiation, thus implicating the involvement of some ribosomal proteins in organogenesis. Consequently, dysregulated functions of these ribosomal proteins could be linked to oncogenesis or neoplastic transformation of human cells. Their suspected roles in carcinogenesis have been reported but not specifically explained for malignancy of the nasopharynx. This is despite the fact that literature since one and half decade ago have documented the association of ribosomal proteins to nasopharyngeal cancer. In this review, we explain the association and contribution of dysregulated expression among a subset of ribosomal proteins to nasopharyngeal oncogenesis. The relationship of these ribosomal proteins with the cancer are explained. We provide information to indicate that the dysfunctional extra-ribosomal activities of specific ribosomal proteins are tightly involved with the molecular pathogenesis of nasopharyngeal cancer albeit mechanisms yet to be precisely defined. The complete knowledge of this will impact future applications in the effective management of nasopharyngeal cancer.

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