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9 results on '"Evgeny Deforzh"'

1. Secreted PGK1 and IGFBP2 contribute to the bystander effect of miR-10b gene editing in glioma

Author

Yanhong Zhang, Rosalia Rabinovsky, Zhiyun Wei, Rachid El Fatimy, Evgeny Deforzh, Bai Luan, Leonid Peshkin, Erik J. Uhlmann, and Anna M. Krichevsky

Subjects
MT: Non-coding RNAs, miR-10b, glioblastoma, gene editing, bystander effect, PGK1, Therapeutics. Pharmacology, RM1-950
Abstract

MicroRNA-10b (miR-10b) is an essential glioma driver and one of the top candidates for targeted therapies for glioblastoma and other cancers. This unique miRNA controls glioma cell cycle and viability via an array of established conventional and unconventional mechanisms. Previously reported CRISPR-Cas9-mediated miR-10b gene editing of glioma cells in vitro and established orthotopic glioblastoma in mouse models demonstrated the efficacy of this approach and its promise for therapy development. However, therapeutic gene editing in patients’ brain tumors may be hampered, among other factors, by the imperfect delivery and distribution of targeting vectors. Here, we demonstrate that miR-10b gene editing in glioma cells triggers a potent bystander effect that leads to the selective cell death of the unedited glioma cells without affecting the normal neuroglial cells. The effect is mediated by the secreted miR-10b targets phosphoglycerate kinase 1 (PGK1) and insulin-like growth factor binding protein 2 (IGFBP2) that block cell-cycle progression and induce glioma cell death. These findings further support the feasibility of therapeutic miR-10b editing without the need to target every cell of the tumor.

Published
2023
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2. A nuclear function for an oncogenic microRNA as a modulator of snRNA and splicing

Author

Rachid El Fatimy, Yanhong Zhang, Evgeny Deforzh, Mahalakshmi Ramadas, Harini Saravanan, Zhiyun Wei, Rosalia Rabinovsky, Nadiya M. Teplyuk, Erik J. Uhlmann, and Anna M. Krichevsky

Subjects
miR-10b, Glioblastoma, Nucleus, U6 snRNA, Splicing machinery, CDC42, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background miRNAs are regulatory transcripts established as repressors of mRNA stability and translation that have been functionally implicated in carcinogenesis. miR-10b is one of the key onco-miRs associated with multiple forms of cancer. Malignant gliomas exhibit particularly striking dependence on miR-10b. However, despite the therapeutic potential of miR-10b targeting, this miRNA’s poorly investigated and largely unconventional properties hamper the clinical translation. Methods We utilized Covalent Ligation of Endogenous Argonaute-bound RNAs and their high-throughput RNA sequencing to identify miR-10b interactome and a combination of biochemical and imaging approaches for target validation. They included Crosslinking and RNA immunoprecipitation with spliceosomal proteins, a combination of miRNA FISH with protein immunofluorescence in glioma cells and patient-derived tumors, native Northern blotting, and the transcriptome-wide analysis of alternative splicing. Results We demonstrate that miR-10b binds to U6 snRNA, a core component of the spliceosomal machinery. We provide evidence of the direct binding between miR-10b and U6, in situ imaging of miR-10b and U6 co-localization in glioma cells and tumors, and biochemical co-isolation of miR-10b with the components of the spliceosome. We further demonstrate that miR-10b modulates U6 N-6-adenosine methylation and pseudouridylation, U6 binding to splicing factors SART3 and PRPF8, and regulates U6 stability, conformation, and levels. These effects on U6 result in global splicing alterations, exemplified by the altered ratio of the isoforms of a small GTPase CDC42, reduced overall CDC42 levels, and downstream CDC42 -mediated effects on cell viability. Conclusions We identified U6 snRNA, the key RNA component of the spliceosome, as the top miR-10b target in glioblastoma. We, therefore, present an unexpected intersection of the miRNA and splicing machineries and a new nuclear function for a major cancer-associated miRNA.

Published
2022
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3. Glioblastoma-Derived Extracellular Vesicles Facilitate Transformation of Astrocytes via Reprogramming Oncogenic Metabolism

Author

Ailiang Zeng, Zhiyun Wei, Rosalia Rabinovsky, Hyun Jung Jun, Rachid El Fatimy, Evgeny Deforzh, Ramil Arora, Yizheng Yao, Shun Yao, Wei Yan, Erik J. Uhlmann, Alain Charest, Yongping You, and Anna M. Krichevsky

Subjects
Biological Sciences, Cell Biology, Cancer, Science
Abstract

Summary: Glioblastoma (GBM) may arise from astrocytes through a multistep process involving a progressive accumulation of mutations. We explored whether GBM-derived extracellular vesicles (EVs) may facilitate neoplastic transformation and malignant growth of astrocytes. We utilized conditioned media (CM) of cultured glioma cells, its sequential filtration, diverse cell-based assays, RNA sequencing, and metabolic assays to compare the effects of EV-containing and EV-depleted CM. GBM EVs facilitated the neoplastic growth of pre-transformed astrocytes but not normal human or mouse astrocytes. They induced proliferation, self-renewal, and colony formation of pre-transformed astrocytes and enhanced astrocytoma growth in a mouse allograft model. GBM EVs appear to reprogram astrocyte metabolism by inducing a shift in gene expression that may be partly associated with EV-mediated transfer of full-length mRNAs encoding ribosomal proteins, oxidative phosphorylation, and glycolytic factors. Our study suggests an EV/extracellular RNA (exRNA)-mediated mechanism that contributes to astrocyte transformation via metabolic reprograming and implicates horizontal mRNA transfer.

Published
2020
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4. Inhibition of the epigenetically activated miR-483-5p/IGF-2 pathway results in rapid loss of meningioma tumor cell viability

Author

Erik J. Uhlmann, Charles E. Mackel, Evgeny Deforzh, Rosalia Rabinovsky, Priscilla K. Brastianos, Hemant Varma, Rafael A. Vega, and Anna M. Krichevsky

Subjects
Cancer Research, Neurology, Oncology, Neurology (clinical)
Abstract

Purpose Meningioma is the most common primary central nervous system tumor often causing serious complications, and presently no medical treatment is available. The goal of this study was to discover miRNAs dysregulated in meningioma, and explore miRNA-associated pathways amenable for therapeutic interventions. Methods Small RNA sequencing was performed on meningioma tumor samples to study grade-dependent changes in microRNA expression. Gene expression was analyzed by chromatin marks, qRT-PCR and western blot. miRNA modulation, anti-IGF-2 neutralizing antibodies, and inhibitors against IGF1R were evaluated in a tumor-derived primary cultures of meningioma cells. Results Meningioma tumor samples showed high, grade-dependent expression of miR-483-5p, associated with high mRNA and protein expression of its host gene IGF-2. Inhibition of miR-483-5p reduced the growth of cultured meningioma cells, whereas a miR-483 mimic increased cell proliferation. Similarly, inhibition of this pathway with anti-IGF-2 neutralizing antibodies reduced meningioma cell proliferation. Small molecule tyrosine kinase inhibitor blockade of the IGF-2 receptor (IGF1R) resulted in rapid loss of viability of cultured meningioma tumor-derived cells, suggesting that autocrine IGF-2 feedback is obligatory for meningioma tumor cell survival and growth. The observed IGF1R-inhibitory IC50 for GSK1838705A and ceritinib in cell-based assays along with the available pharmacokinetics data predicted that effective drug concentration could be achieved in vivo as a new medical treatment of meningioma. Conclusion Meningioma cell growth is critically dependent on autocrine miR-483/IGF-2 stimulation and the IGF-2 pathway provides a feasible meningioma treatment target.

Published
2023
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5. Promoter and enhancer RNAs regulate chromatin reorganization and activation of miR-10b/HOXD locus, and neoplastic transformation in glioma

Author

Evgeny Deforzh, Erik J. Uhlmann, Eashita Das, Aleksandra Galitsyna, Ramil Arora, Harini Saravanan, Rosalia Rabinovsky, Aditya D. Wirawan, Nadiya M. Teplyuk, Rachid El Fatimy, Sucika Perumalla, Anirudh Jairam, Zhiyun Wei, Leonid Mirny, and Anna M. Krichevsky

Subjects
Homeodomain Proteins, Cell Biology, Glioma, Article, Chromatin, Gene Expression Regulation, Neoplastic, MicroRNAs, Cell Transformation, Neoplastic, Cell Line, Tumor, Humans, RNA, Long Noncoding, Glioblastoma, Molecular Biology, Transcription Factors, Cell Proliferation
Abstract

miR-10b is silenced in normal neuroglial cells of the brain but commonly activated in glioma, where it assumes an essential tumor-promoting role. We demonstrate that the entire miR-10b-hosting HOXD locus is activated in glioma via the cis-acting mechanism involving 3D chromatin reorganization and CTCF-cohesin-mediated looping. This mechanism requires two interacting lncRNAs, HOXD-AS2 and LINC01116, one associated with HOXD3/HOXD4/miR-10b promoter and another with the remote enhancer. Knockdown of either lncRNA in glioma cells alters CTCF and cohesin binding, abolishes chromatin looping, inhibits the expression of all genes within HOXD locus, and leads to glioma cell death. Conversely, in cortical astrocytes, enhancer activation is sufficient for HOXD/miR-10b locus reorganization, gene derepression, and neoplastic cell transformation. LINC01116 RNA is essential for this process. Our results demonstrate the interplay of two lncRNAs in the chromatin folding and concordant regulation of miR-10b and multiple HOXD genes normally silenced in astrocytes and triggering the neoplastic glial transformation.

Published
2021

6. Glioblastoma-Derived Extracellular Vesicles Facilitate Transformation of Astrocytes via Reprogramming Oncogenic Metabolism

Author

Wei Yan, Shun Yao, Zhiyun Wei, Rosalia Rabinovsky, Ramil Arora, Yizheng Yao, Anna M. Krichevsky, Alain Charest, Hyun Jung Jun, Evgeny Deforzh, Ailiang Zeng, Erik J. Uhlmann, Yongping You, and Rachid El Fatimy

Subjects
0301 basic medicine, Messenger RNA, Multidisciplinary, Chemistry, Cell, RNA, 02 engineering and technology, Cell Biology, Biological Sciences, 021001 nanoscience & nanotechnology, Article, Cell biology, 03 medical and health sciences, 030104 developmental biology, medicine.anatomical_structure, Gene expression, medicine, Neoplastic transformation, lcsh:Q, 0210 nano-technology, lcsh:Science, Reprogramming, Astrocyte, Extracellular RNA, Cancer
Abstract

Summary Glioblastoma (GBM) may arise from astrocytes through a multistep process involving a progressive accumulation of mutations. We explored whether GBM-derived extracellular vesicles (EVs) may facilitate neoplastic transformation and malignant growth of astrocytes. We utilized conditioned media (CM) of cultured glioma cells, its sequential filtration, diverse cell-based assays, RNA sequencing, and metabolic assays to compare the effects of EV-containing and EV-depleted CM. GBM EVs facilitated the neoplastic growth of pre-transformed astrocytes but not normal human or mouse astrocytes. They induced proliferation, self-renewal, and colony formation of pre-transformed astrocytes and enhanced astrocytoma growth in a mouse allograft model. GBM EVs appear to reprogram astrocyte metabolism by inducing a shift in gene expression that may be partly associated with EV-mediated transfer of full-length mRNAs encoding ribosomal proteins, oxidative phosphorylation, and glycolytic factors. Our study suggests an EV/extracellular RNA (exRNA)-mediated mechanism that contributes to astrocyte transformation via metabolic reprograming and implicates horizontal mRNA transfer., Graphical Abstract, Highlights • Extracellular vesicles (EVs) shed by glioma cells are taken up by astrocytes • Glioma EVs facilitate astrocyte transformation and tumor growth • EVs reprogram glycolysis and oxidative phosphorylation of transformed astrocytes • mRNAs coding ribosomal proteins and other factors are dispersed via EVs, Biological Sciences; Cell Biology; Cancer

Published
2020

7. IMP-3 protects the mRNAs of cyclins D1 and D3 from GW182/AGO2-dependent translational repression

Author

Jeremie Kropp, Anna Polesskaya, Evgeny Deforzh, Marie Vandamme, Thaiz Rivera Vargas, Guillaume Pinna, Institut de Biologie et de Technologies de Saclay ( IBITECS ), Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), Régulation post-transcriptionnelle de l’expression des gènes par les protéines se liant à l’ARN ( RPTEG ), Département Biologie des Génomes ( DBG ), Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Sud - Paris 11 ( UP11 ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Sud - Paris 11 ( UP11 ) -Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Sud - Paris 11 ( UP11 ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Sud - Paris 11 ( UP11 ), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Sud - Paris 11 ( UP11 ), PARi ( PARI ), Département Plateforme ( PF I2BC ), Institut de Biologie et de Technologies de Saclay (IBITECS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Régulation post-transcriptionnelle de l’expression des gènes par les protéines se liant à l’ARN (RPTEG), Département Biologie des Génomes (DBG), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Lipides - Nutrition - Cancer (U866) (LNC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), PARi (PARI), Département Plateforme (PF I2BC), and Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)

Subjects
0301 basic medicine, Cancer Research, Cyclin G1, [SDV]Life Sciences [q-bio], Biology, Autoantigens, ELAV-Like Protein 1, 03 medical and health sciences, RNA interference, Cell Line, Tumor, Polysome, Gene expression, Humans, Cyclin D1, RNA, Messenger, Cyclin D3, Eukaryotic Initiation Factors, RNA, Small Interfering, Nuclear Factor 90 Proteins, 3' Untranslated Regions, Gene, Cyclin, [ SDV ] Life Sciences [q-bio], RNA-Binding Proteins, PTBP1, biochemical phenomena, metabolism, and nutrition, Cell cycle, Molecular biology, Cell biology, enzymes and coenzymes (carbohydrates), 030104 developmental biology, Oncology, Protein Biosynthesis, Argonaute Proteins, RNA Interference, Nuclear localization sequence
Abstract

International audience; IGF-2 mRNA binding protein 3 (IGF2BP3, IMP-3) is a well-known post-transcriptional regulatory factor of gene expression, mainly involved in embryonic development and oncogenesis. We have previously demonstrated that a subset of IMP-3 targets, such as the mRNAs of cyclins D1, D3 and G1, are positively regulated by IMP-3, and that this regulation depends on nuclear localization of IMP-3. In the present study, we show that as a first step following a knock-down of IMP-3, the protein levels of the cyclins rapidly decrease, while their mRNAs remain stable and associated with the polyribosomes, though not translated. We have elucidated the molecular mechanisms of this regulation, demonstrating that IMP-3 and its protein partners ILF3/NF90 and PTBP1 bind to the 3'UTRs of the cyclin mRNAs and protect them from the translational repression induced by miRNA-dependent recruitment of AGO2/GW182 complex in human cancer cells.

Published
2016
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8. The WEE1 regulators CPEB1 and miR-15b switch from inhibitor to activators at G2/M

Author

Regina Groisman, Linda L. Pritchard, Annick Harel-Bellan, Cindy Degerny, Sylvain Cuvellier, Evgeny Deforzh, Andrii Vislovukh, Irina Groisman, Gueorgui Kratassiouk, Qingwei Meng, PARi (PARI), Département Plateforme (PF I2BC), Institut de Biologie Intégrative de la Cellule (I2BC), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Institut de Biologie Intégrative de la Cellule (I2BC), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay, Génétique moléculaire et destin cellulaire (FRE 3377), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Translation Mechanisms, Institute of Molecular Biology and Genetics of National Academy of Sciences of Ukraine, The Breast Department, Third Affiliated Hospital of Harbin Medical University, Laboratoire Epigénétique et Cancer (LEC), Département Biologie des Génomes (DBG), Régulation post-transcriptionnelle de l’expression des gènes par les protéines se liant à l’ARN (RPTEG), PARi ( PARI ), Département Plateforme ( PF I2BC ), Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Sud - Paris 11 ( UP11 ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Sud - Paris 11 ( UP11 ) -Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Sud - Paris 11 ( UP11 ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Sud - Paris 11 ( UP11 ), Génétique moléculaire et destin cellulaire ( FRE 3377 ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Centre National de la Recherche Scientifique ( CNRS ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire Epigénétique et Cancer ( LEC ), Département Biologie des Génomes ( DBG ), Régulation post-transcriptionnelle de l’expression des gènes par les protéines se liant à l’ARN ( RPTEG ), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Sud - Paris 11 (UP11), and Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Untranslated region, Polyadenylation, RISC complex, [SDV]Life Sciences [q-bio], Cell Cycle Proteins, Biology, 03 medical and health sciences, 0302 clinical medicine, RNA interference, Report, Translational regulation, Humans, WEE1, Cell Cycle Protein, Molecular Biology, mRNA Cleavage and Polyadenylation Factors, miR-15b, Messenger RNA, [ SDV ] Life Sciences [q-bio], Base Sequence, Nuclear Proteins, cytoplasmic polyadenylation, Cell Biology, Protein-Tyrosine Kinases, Cell cycle, Molecular biology, translational regulation, Cell biology, G2 Phase Cell Cycle Checkpoints, MicroRNAs, 030104 developmental biology, 030220 oncology & carcinogenesis, RNA Interference, cell cycle, CPEB1, HeLa Cells, Transcription Factors, Developmental Biology
Abstract

International audience; MicroRNAs (miRNAs) in the AGO-containing RISC complex control messenger RNA (mRNA) translation by binding to mRNA 3' untranslated region (3'UTR). The relationship between miRNAs and other regulatory factors that also bind to mRNA 3'UTR, such as CPEB1 (cytoplasmic polyadenylation element-binding protein), remains elusive. We found that both CPEB1 and miR-15b control the expression of WEE1, a key mammalian cell cycle regulator. Together, they repress WEE1 protein expression during G1 and S-phase. Interestingly, the 2 factors lose their inhibitory activity at the G2/M transition, at the time of the cell cycle when WEE1 expression is maximal, and, moreover, rather activate WEE1 translation in a synergistic manner. Our data show that translational regulation by RISC and CPEB1 is essential in cell cycle control and, most importantly, is coordinated, and can be switched from inhibition to activation during the cell cycle.

Published
2016
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9. The WEE1 regulators CPEB1 and miR-15b switch from inhibitor to activators at G2/M

Author

Gueorgui Kratassiouk, Linda L. Pritchard, Sylvain Cuvellier, Andrii Vislovukh, Qingwei Meng, Regina Groisman, Cindy Degerny, Evgeny Deforzh, Annick Harel-Bellan, Irina Groisman, Gueorgui Kratassiouk, Linda L. Pritchard, Sylvain Cuvellier, Andrii Vislovukh, Qingwei Meng, Regina Groisman, Cindy Degerny, Evgeny Deforzh, Annick Harel-Bellan, and Irina Groisman

Abstract

MicroRNAs (miRNAs) in the AGO-containing RISC complex control messenger RNA (mRNA) translation by binding to mRNA 3′ untranslated region (3′UTR). The relationship between miRNAs and other regulatory factors that also bind to mRNA 3′UTR, such as CPEB1 (cytoplasmic polyadenylation element-binding protein), remains elusive. We found that both CPEB1 and miR-15b control the expression of WEE1, a key mammalian cell cycle regulator. Together, they repress WEE1 protein expression during G1 and S-phase. Interestingly, the 2 factors lose their inhibitory activity at the G2/M transition, at the time of the cell cycle when WEE1 expression is maximal, and, moreover, rather activate WEE1 translation in a synergistic manner. Our data show that translational regulation by RISC and CPEB1 is essential in cell cycle control and, most importantly, is coordinated, and can be switched from inhibition to activation during the cell cycle.

Published
2016
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