ArticleNature cell biology2019
IMP dehydrogenase-2 drives aberrant nucleolar activity and promotes tumorigenesis in glioblastoma.
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Article in Nature cell biology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 115 papers.
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115citing papers in PubMed
8.8field-weighted citation impact, top 1% of its field
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Who cites it
115 citing papers in PubMed, 174 citations in OpenAlex.
- PTEN-loss confers dependence on the guanylate synthesis enzyme IMPDH in T-cell acute lymphoblastic leukemia.EMBO molecular medicine · 2026Article
- GTP biosynthesis is a therapeutic vulnerability in Rac1-mutant melanoma.bioRxiv : the preprint server for biology · 2026Article
- Dynamic control of nucleotide metabolism in physiology and disease.Nature cell biology · 2026Review
- Nucleotide Metabolism in Health and Disease.MedComm · 2026Review
- A nucleolar stress gene signature enables quantitative scoring across multi-omics contexts.Communications biology · 2026Article
- IMP metabolic mechanisms and IMPDH targeting strategies in tumor metabolic reprogramming and therapy (Review).International journal of molecular medicine · 2026Review
- The oncogenic control of nucleotide synthesis.Oncogenesis · 2026Review
- Dynamic Monitoring of Content Variation of Guanosine Triphosphate in Single Cells under External Stimulus with Functionalized Fluorescent/Photothermal NbChemical & biomedical imaging · 2026Article
- Nucleoli-localized KANSL2 as an epigenetic regulator of ribosome biogenesis in glioblastoma cells.Communications biology · 2026Article
- Digital twins for in vivo metabolic flux estimations in patients with brain cancer.Cell metabolism · 2026Article
- DHL-11, a novel prieurianin-type limonoid isolated fromActa pharmaceutica Sinica. B · 2026Article
- PTEN-loss confers dependence on the guanylate synthesis enzyme IMPDH in T-cell acute lymphoblastic leukemia.bioRxiv : the preprint server for biology · 2025Article
- IMPDH and GTP Metabolism in Cancer: Mechanisms, Regulation, and Translational Scope.Cancer science · 2025Review
- Adaptive nuclear GTP synthesis promotes glioblastoma treatment resistance and is a targetable vulnerability in patients.medRxiv : the preprint server for health sciences · 2025Article
- RNase H-sensitive accumulation of APOBEC3B in a nucleolus after DNA damage.Bioscience reports · 2025Article
- A Novel Allosteric Inhibitor Targeting IMPDH at Y233 Overcomes Resistance to Tyrosine Kinase Inhibitors in Lymphoma.Cancers · 2025Article
- Temozolomide-Derived AIC Is Incorporated into Purine Synthesis in Glioblastoma.Chemical research in toxicology · 2025Article
- Targeting ribosomes reprograms the tumour microenvironment and augments cancer immunotherapy.British journal of cancer · 2025Article
- Streptococcus gallolyticus supernatant induces M2 macrophage polarization and activates IL-17 F signaling in colorectal tumorigenesis.Gut pathogens · 2025Article
- Y12C mutation disrupts IMPDH cytoophidia and alters cancer metabolism.The FEBS journal · 2025Article
55 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
57 authors at 20 institutions in 6 countries.
Satoshi KofujiDivision of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Akiyoshi HirayamaInstitute for Advanced Biosciences, Keio University, Tsuruoka, Japan.
Alexander Otto EberhardtInstitute of Biochemistry and Biophysics, Center for Molecular Biomedicine, Friedrich Schiller University Jena, Jena, Germany.
Risa KawaguchiDivision of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA.ORCID http://orcid.org/0000-0003-1764-5721
Yuki SugiuraDepartment of Biochemistry, Keio University School of Medicine, Tokyo, Japan.
Oltea SampetreanDivision of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan.ORCID http://orcid.org/0000-0001-5783-1049
Yoshiki IkedaDivision of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Mikako WarrenDivision of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Naoya SakamotoGraduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
Shuji KitaharaDepartment of Anatomy and Developmental Biology, Tokyo Women's Medical University School of Medicine, Tokyo, Japan.ORCID http://orcid.org/0000-0002-2904-0319
Hirofumi YoshinoDivision of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Daisuke YamashitaDepartment of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA.
Kazutaka SumitaDivision of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Kara WolfeDivision of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Lisa LangeInstitute of Biochemistry and Biophysics, Center for Molecular Biomedicine, Friedrich Schiller University Jena, Jena, Germany.
Satsuki IkedaInstitute for Advanced Biosciences, Keio University, Tsuruoka, Japan.
Hiroko ShimadaDivision of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Noriaki MinamiDivision of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan.
Akshiv MalhotraDivision of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Shin MoriokaGraduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
Yuki BanGraduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
Maya AsanoGraduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
Victoria L FlanaryDepartment of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA.
Annmarie RamkissoonCancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Lionel M L ChowCancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Juri KiyokawaDepartment of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Tomoyuki MashimoDepartment of Internal Medicine; Harold C. Simmons Comprehensive Cancer Center; Annette G. Strauss Center for Neuro-Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Greg LuceyDivision of Neuropathology, Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Sergey MareninovDivision of Neuropathology, Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Tatsuya OzawaDivision of Human Biology, Solid Tumor and Translational Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Nobuyuki OnishiDivision of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan.
Koichi OkumuraDivision of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Jumpei TerakawaDivision of Transgenic Animal Science, Advanced Science Research Center, Kanazawa University, Kanazawa, Japan.
Takiko DaikokuDivision of Transgenic Animal Science, Advanced Science Research Center, Kanazawa University, Kanazawa, Japan.
Trisha Wise-DraperDivision of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Nazanin MajdDepartment of Neurology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Kaori KofujiDivision of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Mika SasakiDivision of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Masaru MoriInstitute for Advanced Biosciences, Keio University, Tsuruoka, Japan.
Yonehiro KanemuraDepartment of Biomedical Research and Innovation, Institute for Clinical Research, National Hospital Organization Osaka National Hospital, Osaka, Japan.
Eric P SmithDepartment of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Dimitrios AnastasiouCancer Metabolism Laboratory, The Francis Crick Institute, London, UK.ORCID http://orcid.org/0000-0002-1269-843X
Hiroaki WakimotoDepartment of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0000-0001-8225-241X
Eric C HollandDivision of Human Biology, Solid Tumor and Translational Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.ORCID http://orcid.org/0000-0002-3792-7120
William H YongDivision of Neuropathology, Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Craig HorbinskiDepartment of Pathology, University of Kentucky College of Medicine, Lexington, KY, USA.
Ichiro NakanoDepartment of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA.
Ralph J DeBerardinisHoward Hughes Medical Institute; Children's Medical Center Research Institute; Department of Pediatrics and Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Robert M BachooDepartment of Internal Medicine; Harold C. Simmons Comprehensive Cancer Center; Annette G. Strauss Center for Neuro-Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Paul S MischelLudwig Institute for Cancer Research; Department of Pathology; Moores Cancer Center, University of California San Diego School of Medicine, La Jolla, CA, USA.ORCID http://orcid.org/0000-0002-4560-2211
Wataru YasuiGraduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
Makoto SuematsuDepartment of Biochemistry, Keio University School of Medicine, Tokyo, Japan.ORCID http://orcid.org/0000-0002-7165-6336
Hideyuki SayaDivision of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan.ORCID http://orcid.org/0000-0001-6610-1902
Tomoyoshi SogaInstitute for Advanced Biosciences, Keio University, Tsuruoka, Japan.
Ingrid GrummtDivision of Molecular Biology of the Cell II, German Cancer Research Center, DKFZ-ZMBH Alliance, Heidelberg, Germany.
Holger BierhoffInstitute of Biochemistry and Biophysics, Center for Molecular Biomedicine, Friedrich Schiller University Jena, Jena, Germany.
Atsuo T SasakiDivision of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA. atsuo.sasaki@uc.edu.ORCID http://orcid.org/0000-0003-2963-4501
University of Cincinnati Medical Center · USKeio University · JPHiroshima University · JPLeibniz Institute on Aging - Fritz Lipmann Institute (FLI) · DEUniversity of Alabama at Birmingham · USUniversity of California, Los Angeles · USCenter for Neuro-Oncology · USCincinnati Children's Hospital Medical Center · USFred Hutch Cancer Center · USHarvard University · USKanazawa University · JPAllen Institute for Brain Science · USGerman Cancer Research Center · DEHoward Hughes Medical Institute · USNational Institute of Advanced Industrial Science and Technology · JPNorthwestern University · USOsaka National Hospital · JPThe Francis Crick Institute · GBTokyo Women's Medical University · JPUniversity of California San Diego · US
Funding
UCLA SPORE in Brain CancerP50CA211015 · NCI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI David A. Nathanson · 2017 to 2026
$25.2MSTINGing GBM: A First-in- Man Clinical Trial in Surgical Resectable Recurrent GBMP50CA221747 · NCI · NORTHWESTERN UNIVERSITY AT CHICAGO · PI Pouya Jamshidi · 2018 to 2026
$21.4MMetabolic Regulators of Tumor Growth and ProgressionR35CA220449 · NCI · UT SOUTHWESTERN MEDICAL CENTER · PI RALPH J DEBERARDINIS · 2017 to 2026
$9.4MThe role of mTORC2 in reprogramming cancer cell metabolismR01NS073831 · NINDS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI MISCHEL, PAUL S · 2011 to 2020
$3.4MTissue Factor as a Key Determinant of IDH1 Mutant versus IDH1 Wild-type Glioma Thrombosis and MalignancyR01NS102669 · NINDS · NORTHWESTERN UNIVERSITY AT CHICAGO · PI HORBINSKI, CRAIG MICHAEL · 2017 to 2021
$1.7MTargeting the Novel PI5P4K Pathway to Induce Glioblastoma SenescenceR01NS089815 · NINDS · UNIVERSITY OF CINCINNATI · PI SASAKI, ATSUO · 2014 to 2018
$1.7MSynthetic Lethal Combination of KRP203/Fingolimod with PI3K signaling for glioblastoma multiforme death by catastrophic vacuolizationR21NS100077 · NINDS · UNIVERSITY OF CINCINNATI · PI SASAKI, ATSUO · 2016 to 2017
$448kRadiation-Induced Crosstalk of Immune and Glioma Stem CellsR01NS107071 · NINDS · UNIVERSITY OF ALABAMA AT BIRMINGHAM · PI NAKANO, ICHIRO · 2019 to 2019
$320kNCI NIH HHS P50 CA211015NCI NIH HHS P50 CA221747NCI NIH HHS R35 CA220449NINDS NIH HHS R01 NS073831NINDS NIH HHS R01 NS089815NINDS NIH HHS R01 NS102669NINDS NIH HHS R01 NS107071NINDS NIH HHS R21 NS100077Wellcome Trust FC001033
Abstract
In many cancers, high proliferation rates correlate with elevation of rRNA and tRNA levels, and nucleolar hypertrophy. However, the underlying mechanisms linking increased nucleolar transcription and tumorigenesis are only minimally understood. Here we show that IMP dehydrogenase-2 (IMPDH2), the rate-limiting enzyme for de novo guanine nucleotide biosynthesis, is overexpressed in the highly lethal brain cancer glioblastoma. This leads to increased rRNA and tRNA synthesis, stabilization of the nucleolar GTP-binding protein nucleostemin, and enlarged, malformed nucleoli. Pharmacological or genetic inactivation of IMPDH2 in glioblastoma reverses these effects and inhibits cell proliferation, whereas untransformed glia cells are unaffected by similar IMPDH2 perturbations. Impairment of IMPDH2 activity triggers nucleolar stress and growth arrest of glioblastoma cells even in the absence of functional p53. Our results reveal that upregulation of IMPDH2 is a prerequisite for the occurance of aberrant nucleolar function and increased anabolic processes in glioblastoma, which constitutes a primary event in gliomagenesis.
Indexed as
CarcinogenesisCell Line, TumorCell NucleolusCell ProliferationCell Transformation, NeoplasticGlioblastomaHumansIMP DehydrogenaseRNA, RibosomalIMP DehydrogenaseIMPDH2 protein, humanRNA, Ribosomal
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