Regulation of 4E-BP1 activity in the mammalian oocyte

Jansová, Denisa; Končická, Markéta; Tetkova, Anna; Malı́k, Radek; Llano, Edgar Del; Kubelka, Michal; Šušor, Andrej

doi:10.1080/15384101.2017.1295178

Cited by 38 publications

(58 citation statements)

References 76 publications

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“…In conclusion, using a chemoproteomic approach, we have discovered that CDK4 phosphorylates 4E-BP1 during the M-to-G 1 transition, thereby maintaining capdependent translation. These findings shed further light on the cell cycle-dependent phosphorylation of 4E-BP1, the regulation of which was previously reported to be mediated by CDK1 and CDK12 in mitotic cells [29,61,62], and PLK1 and CDK1 in cells undergoing meiosis [22,32,[63][64][65]. Given this newly discovered role of CDK4, it is likely that inhibition of mitotic 4E-BP1 phosphorylation is a previously unknown function of CDK4/6 inhibitors such as palbociclib, and may explain the synergy between these drugs and mTOR inhibitors [66][67][68][69][70][71][72].…”

Section: Discussionsupporting

confidence: 69%

“…CDK12, via phosphorylation of 4E-BP1 at S65 and T70, cooperates with mTORC1 to drive selective translation of proteins involved in maintenance of the mitotic genome [29]. Additionally, CDK1, the master regulator of the G 2 /M transition, can substitute for mTORC1 to phosphorylate 4E-BP1 at the putative mTORC1 sites to activate cap-dependent translation during mitosis [30,31] and meiosis [32]. A mechanistic investigation of the mitotic phosphorylation of 4E-BP1 uncovered CDK1-mediated phosphorylation of the noncanonical site S83.…”

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confidence: 99%

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Cyclin‐dependent kinase 4 inhibits the translational repressor 4E‐BP1 to promote cap‐dependent translation during mitosis–G1 transition

2019

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Phosphorylation of translational repressor eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) controls the initiation of capdependent translation, a type of protein synthesis that is frequently upregulated in human diseases such as cancer. Because of its critical cellular function, it is not surprising that multiple kinases can post-translationally modify 4E-BP1 to drive aberrant cap-dependent translation. We recently reported a site-selective chemoproteomic method for uncovering kinase-substrate interactions, and using this approach, we discovered the cyclin-dependent kinase (CDK)4 as a new 4E-BP1 kinase. Herein, we describe our extension of this work and reveal the role of CDK4 in modulating 4E-BP1 activity in the transition from mitosis to G1, thereby demonstrating a novel role for this kinase in cell cycle regulation.Cap-dependent translation is an important cellular process that controls the translation of select mRNAs typically encoding for growth factors and oncogenes [1][2][3][4]. The initiation of cap-dependent mRNA translation is governed by the availability of eIF4E, the m 7 GpppX-cap-binding translation initiation factor [5,6]. This protein is highly regulated, primarily through the work of the 4E-BPs, which sequester eIF4E from eIF4G and the eIF4F translation initiation complex [7][8][9][10][11][12][13]. The activity of 4E-binding protein 1 (4E-BP1) is in turn regulated by phosphorylation, where hypophosphorylated 4E-BP1 binds strongly to eIF4E to inhibit translation, while hyperphosphorylated 4E-BP1 releases eIF4E to initiate capdependent translation [13][14][15][16]. For many years, the only validated kinase known to affect 4E-BP1 phosphorylation has been mechanistic target of rapamycin complex 1 (mTORC1), which was shown to hierarchically phosphorylate 4E-BP1 at T37 and T46 followed by T70 and S65 [14,15,17,18]. However, several findings have called into question the exclusivity of mTORC1 for each of these phosphorylation sites [19], namely reports demonstrating that other unknown kinases can also phosphorylate 4E-BP1 to stimulate cap-dependent translation [20][21][22], particularly in cases of mTOR inhibitor drug resistance [23][24][25][26].Recently, our laboratory has developed a chemoproteomic pipeline by which to identify site-specific kinase-substrate interactions, Phosphosite-Accurate kinase-substrate cross(X)linking Assay or PhAXA [27]. Using this methodology, we discovered that cyclin-dependent kinase 4 (CDK4), which is primarily responsible for controlling the cell cycle checkpoint at the G 1 /S transition through phosphorylation of the retinoblastoma tumor suppressor protein (Rb) Abbreviations 4E-BP1, 4E-binding protein 1; CDK, cyclin-dependent kinase; FDR, false discovery rate; mTORC1, mechanistic target of rapamycin complex 1; PSMs, peptide-spectrum matches; WT, wild-type.

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Section: Discussionsupporting

confidence: 69%

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confidence: 99%

Cyclin‐dependent kinase 4 inhibits the translational repressor 4E‐BP1 to promote cap‐dependent translation during mitosis–G1 transition

2019

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“…5 The current study adds new information by investigating the role of CDK1 in the phosphorylation of 4E-BP1 in mouse oocytes. 2 Using specific kinase inhibitors, they showed that CDK1 and mTOR kinases are the main positive regulators of 4E-BP1 phosphorylation following NEBD (Fig. 1).…”

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confidence: 98%

“…In this volume of the Cell Cycle the study by Jansova et al provides new insight into the role of the eukaryotic initiation factor 4E-Binding Protein 1 (4E-BP1) in meiotic spindle formation in the mouse oocyte. 2 Phosphorylation of 4E-BP1 at sites that control its binding to eIF4E, and consequently its ability to inhibit translation, has been shown to be dynamic and finely regulated in space in mitotic and meiotic spindle. 3,4 In particular, it has been proposed that the localization of 4E-BP1 isoforms that have been phosphorylated at these sites at the spindle pole or on the spindle represents a novel mechanism to localize protein synthesis from mRNAs that are localized at the spindle.…”

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confidence: 99%

“…Which mRNAs are actively translated in this spatial and temporal context? The integration of knowledge about 4E-BP1-phosphorylation at different scales (molecular / structural 7 and intracellular compartments [2][3][4][5][6] ) opens up a promising field of investigation for systemic approaches that focus on spatiotemporal control of mRNA translation. Several characteristics of the mammalian oocyte meiotic maturation system including its size and round shape, synchronism and asymmetry of meiotic divisions and links between meiotic divisions and translation, make it an interesting future model in this context.…”

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Translation regulator ballet in meiotic spindle

Cormier

2017

Cell Cycle

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Translational Regulation in the Mammalian Oocyte

Šušor

Kubelka

2017

Results and Problems in Cell Differentiation

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Fully grown oocytes arrest meiosis at prophase I and deposit maternal RNAs. A subset of maternal transcripts is stored in a dormant state in the oocyte, and the timely driven translation of specific mRNAs guides meiotic progression, the oocyte-embryo transition, and early embryo development. In the absence of transcription, the regulation of gene expression in oocytes is controlled almost exclusively at the level of transcriptome and proteome stabilization and at the level of protein synthesis.This chapter focuses on the recent findings on RNA distribution related to the temporal and spatial translational control of the meiotic cycle progression in mammalian oocytes. We discuss the most relevant mechanisms involved in the organization of the oocyte's maternal transcriptome storage and localization, and the regulation of translation, in correlation with the regulation of oocyte meiotic progression.

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Regulation of 4E-BP1 activity in the mammalian oocyte

Cited by 38 publications

References 76 publications

Cyclin‐dependent kinase 4 inhibits the translational repressor 4E‐BP1 to promote cap‐dependent translation during mitosis–G1 transition

Cyclin‐dependent kinase 4 inhibits the translational repressor 4E‐BP1 to promote cap‐dependent translation during mitosis–G1 transition

Translation regulator ballet in meiotic spindle

Translational Regulation in the Mammalian Oocyte

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