scholarly journals Translational regulation of the cell cycle: when, where, how and why?

2011 ◽  
Vol 366 (1584) ◽  
pp. 3638-3652 ◽  
Author(s):  
Iva Kronja ◽  
Terry L. Orr-Weaver
Keyword(s):  
Cell Cycle ◽  
Translational Control ◽  
Translational Regulation ◽  
Cell Cycle Progression ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Early Embryogenesis ◽  
Model Organisms ◽  
Translational Efficiency ◽  
Cell Cycle Regulators

Translational regulation contributes to the control of archetypal and specialized cell cycles, such as the meiotic and early embryonic cycles. Late meiosis and early embryogenesis unfold in the absence of transcription, so they particularly rely on translational repression and activation of stored maternal mRNAs. Here, we present examples of cell cycle regulators that are translationally controlled during different cell cycle and developmental transitions in model organisms ranging from yeast to mouse. Our focus also is on the RNA-binding proteins that affect cell cycle progression by recognizing special features in untranslated regions of mRNAs. Recent research highlights the significance of the cytoplasmic polyadenylation element-binding protein (CPEB). CPEB determines polyadenylation status, and consequently translational efficiency, of its target mRNAs in both transcriptionally active somatic cells as well as in transcriptionally silent mature Xenopus oocytes and early embryos. We discuss the role of CPEB in mediating the translational timing and in some cases spindle-localized translation of critical regulators of Xenopus oogenesis and early embryogenesis. We conclude by outlining potential directions and approaches that may provide further insights into the translational control of the cell cycle.

scholarly journals CAR-1 and Trailer hitch: driving mRNP granule function at the ER?

2006 ◽  
Vol 173 (2) ◽  
pp. 159-163 ◽  
Author(s):  
Carolyn J. Decker ◽  
Roy Parker
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Fate ◽  
Translational Control ◽  
Translational Regulation ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Spindle Pole ◽  
Axis Formation ◽  
Cell Fate Determination ◽  
Messenger Rnas

The targeting of messenger RNAs (mRNAs) to specific subcellular sites for local translation plays an important role in diverse cellular and developmental processes in eukaryotes, including axis formation, cell fate determination, spindle pole regulation, cell motility, and neuronal synaptic plasticity. Recently, a new conserved class of Lsm proteins, the Scd6 family, has been implicated in controlling mRNA function. Depletion or mutation of members of the Scd6 family, Caenorhabditis elegans CAR-1 and Drosophila melanogaster trailer hitch, lead to a variety of developmental phenotypes, which in some cases can be linked to alterations in the endoplasmic reticulum (ER). Scd6/Lsm proteins are RNA binding proteins and are found in RNP complexes associated with translational control of mRNAs, and these complexes can colocalize with the ER. These findings raise the possibility that localization and translational regulation of mRNAs at the ER plays a role in controlling the organization of this organelle.

scholarly journals Human CPR (Cell Cycle Progression Restoration) Genes Impart a Far– Phenotype on Yeast Cells

Genetics ◽  
1997 ◽  
Vol 147 (3) ◽  
pp. 1063-1076 ◽  
Author(s):  
Michael C Edwards ◽  
Nanette Liegeois ◽  
Joe Horecka ◽  
Ronald A DePinho ◽  
George F Sprague ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Growth Control ◽  
Yeast Cells ◽  
G1 Arrest ◽  
Mating Pheromone ◽  
Cycle Progression ◽  
Yeast Genes

Regulated cell cycle progression depends on the proper integration of growth control pathways with the basic cell cycle machinery. While many of the central molecules such as cyclins, CDKs, and CKIs are known, and many of the kinases and phosphatases that modify the CDKs have been identified, little is known about the additional layers of regulation that impinge upon these molecules. To identify new regulators of cell proliferation, we have selected for human and yeast cDNAs that when overexpressed were capable of specifically overcoming G1 arrest signals from the cell cycle branch of the mating pheromone pathway, while still maintaining the integrity of the transcriptional induction branch. We have identified 13 human CPR (cell cycle progression restoration) genes and 11 yeast OPY (overproduction-induced pheromone-resistant yeast) genes that specifically block the G1 arrest by mating pheromone. The CPR genes represent a variety of biochemical functions including a new cyclin, a tumor suppressor binding protein, chaperones, transcription factors, translation factors, RNA-binding proteins, as well as novel proteins. Several CPR genes require individual CLNs to promote pheromone resistance and those that require CLN3 increase the basal levels of Cln3 protein. Moreover, several of the yeast OPY genes have overlapping functions with the human CPR genes, indicating a possible conservation of roles.

scholarly journals N6-methyladenosine dynamics during early vertebrate embryogenesis

2019 ◽  
Author(s):  
Håvard Aanes ◽  
Dominique Engelsen ◽  
Adeel Manaf ◽  
Endalkachew Ashenafi Alemu ◽  
Cathrine Broberg Vågbø ◽  
...  
Keyword(s):  
Translational Regulation ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Rna Degradation ◽  
Translational Efficiency ◽  
Mrna Levels ◽  
Maternal Transcripts ◽  
Post Transcriptional Regulation ◽  
Genome Activation ◽  
Polyadenylated Mrna

AbstractEarly vertebrate embryogenesis is characterized by extensive post-transcriptional regulation during the maternal-to-zygotic transition. The N6-methyladenosine (m6A) modifications on mRNA have been shown to affect both translation and stability of transcripts. Here we investigate the m6A topology during early vertebrate embryogenesis and its association with polyadenylated mRNA levels. The majority (>70%) of maternal transcripts harbor m6A, and there is a substantial increase of m6A in the polyadenylated mRNA fraction between 0 and 2 hours post fertilization. Notably, we find strong associations between m6A, cytoplasmic polyadenylation and translational efficiency prior to zygotic genome activation (ZGA). Interestingly, the relationship between m6A and translation is strongest for peaks located in the 3’UTR, but not overlapping stop codons. Sequence analyses revealed enrichment of motifs for RNA binding proteins involved in translational regulation and RNA degradation. After ZGA, m6A seem to diminish the effect of miR-430 mediated degradation. The reported results improve our understanding of the combinatorial code behind post-transcriptional mRNA regulation during embryonic reprogramming and early differentiation.

scholarly journals DiSUMO-LIKE Interacts with RNA-Binding Proteins and Affects Cell-Cycle Progression during Maize Embryogenesis

2018 ◽  
Vol 28 (10) ◽  
pp. 1548-1560.e5 ◽  
Author(s):  
Junyi Chen ◽  
Kamila Kalinowska ◽  
Benedikt Müller ◽  
Julia Mergner ◽  
Rainer Deutzmann ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Cycle Progression

scholarly journals Post-translational Control of RNA-Binding Proteins and Disease-Related Dysregulation

2021 ◽  
Vol 8 ◽  
Author(s):  
Alejandro Velázquez-Cruz ◽  
Blanca Baños-Jaime ◽  
Antonio Díaz-Quintana ◽  
Miguel A. De la Rosa ◽  
Irene Díaz-Moreno
Keyword(s):  
Translational Control ◽  
Translational Regulation ◽  
Transcriptional Control ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Physiological Role ◽  
Dynamic Composition ◽  
Mrna Metabolism ◽  
As Stress

Cell signaling mechanisms modulate gene expression in response to internal and external stimuli. Cellular adaptation requires a precise and coordinated regulation of the transcription and translation processes. The post-transcriptional control of mRNA metabolism is mediated by the so-called RNA-binding proteins (RBPs), which assemble with specific transcripts forming messenger ribonucleoprotein particles of highly dynamic composition. RBPs constitute a class of trans-acting regulatory proteins with affinity for certain consensus elements present in mRNA molecules. However, these regulators are subjected to post-translational modifications (PTMs) that constantly adjust their activity to maintain cell homeostasis. PTMs can dramatically change the subcellular localization, the binding affinity for RNA and protein partners, and the turnover rate of RBPs. Moreover, the ability of many RBPs to undergo phase transition and/or their recruitment to previously formed membrane-less organelles, such as stress granules, is also regulated by specific PTMs. Interestingly, the dysregulation of PTMs in RBPs has been associated with the pathophysiology of many different diseases. Abnormal PTM patterns can lead to the distortion of the physiological role of RBPs due to mislocalization, loss or gain of function, and/or accelerated or disrupted degradation. This Mini Review offers a broad overview of the post-translational regulation of selected RBPs and the involvement of their dysregulation in neurodegenerative disorders, cancer and other pathologies.

scholarly journals Cytosolic aspartate aminotransferase moonlights as a ribosome binding modulator of Gcn2 activity during oxidative stress

2021 ◽  
Author(s):  
Robert A. Crawford ◽  
Mark P. Ashe ◽  
Simon J. Hubbard ◽  
Graham D. Pavitt
Keyword(s):  
Oxidative Stress ◽  
Translational Control ◽  
Aspartate Aminotransferase ◽  
Ribosomal Proteins ◽  
Translational Regulation ◽  
Cellular Response ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Stress Sensitivity ◽  
Yeast Cells

AbstractRegulation of translation is a fundamental facet of the cellular response to rapidly changing external conditions. Specific RNA-binding proteins (RBPs) co-ordinate the translational regulation of distinct mRNA cohorts during stress. To identify RBPs with previously under-appreciated roles in translational control, we used polysome profiling and mass spectrometry to identify and quantify proteins associated with translating ribosomes in unstressed yeast cells and during oxidative stress and amino acid starvation, which both induce the integrated stress response (ISR). Over 800 proteins were identified across polysome gradient fractions, including ribosomal proteins, translation factors and many others without previously described translation-related roles, including numerous metabolic enzymes. We identified variations in patterns of polysome enrichment in both unstressed and stressed cells and identified proteins enriched in heavy polysomes during stress. Genetic screening of polysome-enriched RBPs identified the cytosolic aspartate aminotransferase, Aat2, as a ribosome-associated protein whose deletion conferred growth sensitivity to oxidative stress. Loss of Aat2 caused aberrantly high activation of the ISR via enhanced eIF2α phosphorylation and GCN4 activation. Importantly, non-catalytic AAT2 mutants retained polysome association and did not show heightened stress sensitivity. Aat2 therefore has a separate ribosome-associated translational regulatory or ‘moonlighting’ function that modulates the ISR independent of its aspartate aminotransferase activity.

AU-rich element-mediated translational control: complexity and multiple activities of trans-activating factors

2002 ◽  
Vol 30 (6) ◽  
pp. 952-958 ◽  
Author(s):  
T. Zhang ◽  
V. Kruys ◽  
G. Huez ◽  
C. Gueydan
Keyword(s):  
Translational Control ◽  
Cell Activation ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Translational Efficiency ◽  
Cdna Expression Library ◽  
Sequence Specificity ◽  
Expression Library ◽  
Tnf Α

Tumour necrosis factor (TNF)-α mRNA contains an AU-rich element (ARE) in its 3′ untranslated region (3′UTR), which determines its half-life and translational efficiency. In unstimulated macrophages, TNF-α mRNA is repressed translationally, and becomes efficiently translated upon cell activation. Gel retardation experiments and screening of a macrophage cDNA expression library with the TNF-α ARE allowed the identification of TIA-1-related protein (TIAR), T-cell intracellular antigen-1 (TIA-1) and tristetraprolin (TTP) as TNF-α ARE-binding proteins. Whereas TIAR and TIA-1 bind the TNF-α ARE independently of the activation state of macrophages, the TTP-ARE complex is detectable upon stimulation with lipopolysaccharide (LPS). Moreover, treatment of LPS-induced macrophage extracts with phosphatase significantly abrogates TTP binding to the TNF-α ARE, indicating that TTP phosphorylation is required for ARE binding. Carballo, Lai and Blackshear [(1998) Science 281, 1001–1005] showed that TTP was a TNF-α mRNA destabilizer. In contrast, TIA-1, and most probably TIAR, acts as a TNF-α mRNA translational silencer. A two-hybrid screening with TIAR and TIA-1 revealed the capacity of these proteins to interact with other RNA-binding proteins. Interestingly, TIAR and TIA-1 are not engaged in the same interaction, indicating for the first time that TIAR and TIA-1 can be functionally distinct. These findings also suggest that ARE-binding proteins interact with RNA as multimeric complexes, which might define their function and their sequence specificity.

scholarly journals RNA-binding protein CELF6 is cell cycle regulated and controls cancer cell proliferation by stabilizing p21

2019 ◽  
Vol 10 (10) ◽  
Author(s):  
Gang Liu ◽  
Qianwen Zhang ◽  
Li Xia ◽  
Mengjuan Shi ◽  
Jin Cai ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cancer Cell ◽  
Cell Cycle Progression ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Cancer Cell Proliferation ◽  
Cycle Progression ◽  
Specific Alternative ◽  
Cycle Dependent

Abstract CELF6, a member of the CELF family of RNA-binding proteins, regulates muscle-specific alternative splicing and contributes to the pathogenesis of myotonic dystrophy (DM), however the role of CELF6 in cancer cell proliferation is less appreciated. Here, we show that the expression of CELF6 is cell cycle regulated. The cell cycle-dependent expression of CELF6 is mediated through the ubiquitin-proteasome pathway, SCF-β-TrCP recognizes a nonphospho motif in CELF6 and regulates its proteasomal degradation. Overexpression or depletion of CELF6 modulates p21 gene expression. CELF6 binds to the 3′UTR of p21 transcript and increases its mRNA stability. Depletion of CELF6 promotes cell cycle progression, cell proliferation and colony formation whereas overexpression of CELF6 induces G1 phase arrest. The effect of CELF6 on cell proliferation is p53 and/or p21 dependent. Collectively, these data demonstrate that CELF6 might be a potential tumor suppressor, CELF6 regulates cell proliferation and cell cycle progression via modulating p21 stability.

scholarly journals CPEB4 is regulated during cell cycle by ERK2/Cdk1-mediated phosphorylation and its assembly into liquid-like droplets

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Jordina Guillén-Boixet ◽  
Víctor Buzon ◽  
Xavier Salvatella ◽  
Raúl Méndez
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Post Translational Modifications ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Extracellular Signals ◽  
Binding Domains ◽  
M Phase

The four members of the vertebrate CPEB family of RNA-binding proteins share similar RNA-binding domains by which they regulate the translation of CPE-containing mRNAs, thereby controlling cell cycle and differentiation or synaptic plasticity. However, the N-terminal domains of CPEBs are distinct and contain specific regulatory post-translational modifications that presumably differentially integrate extracellular signals. Here we show that CPEB4 activity is regulated by ERK2- and Cdk1-mediated hyperphosphorylation. These phosphorylation events additively activate CPEB4 in M-phase by maintaining it in its monomeric state. In contrast, unphosphorylated CPEB4 phase separates into inactive, liquid-like droplets through its intrinsically disordered regions in the N-terminal domain. This dynamic and reversible regulation of CPEB4 is coordinated with that of CPEB1 through Cdk1, which inactivates CPEB1 while activating CPEB4, thereby integrating phase-specific signal transduction pathways to regulate cell cycle progression.

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