ArticleCell2021
The PP2A-Integrator-CDK9 axis fine-tunes transcription and can be targeted therapeutically in cancer.
Open access · bronzeAbstract read
In one paragraph
Article in Cell, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 118 papers.
0numbers the graph read from it
0cells of the map it votes in
118citing papers in PubMed
14.8field-weighted citation impact, top 1% of its field
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
118 citing papers in PubMed, 211 citations in OpenAlex.
- Phosphoproteomic dysregulation promotes tumor proliferation in Cushing's disease.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Nuclear-targeted GDOWN1 potently suppresses tumors by inducing premature transcription termination and exporting Pol Ⅱ CTD phosphatases to activate RB.Cell death and differentiation · 2026Article
- Targeting CDKs in the RNAPII transcription cycle.Nature reviews. Drug discovery · 2026Review
- Multisite Threonine Phosphorylation in the SPT5 C-Terminal Region 1 Enables Sequence-Dependent Regulation without Global Structural Remodeling.The journal of physical chemistry. B · 2026Article
- Mechanisms of transcription termination across the coding and noncoding loci of the genome.Nature reviews. Molecular cell biology · 2026Review
- CDK9 inhibition sensitizes intrinsically resistantActa pharmaceutica Sinica. B · 2026Article
- ZDHHC17-Mediated CDK4 Palmitoylation Drives Cell Cycle Progression and Orchestrates Cancer Immune Surveillance.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Regulation of RNA transcript elongation in metazoans and its relevance to disease.Nature reviews. Molecular cell biology · 2026Review
- CDK9 inhibition triggers MT2A-dependent apoptosis in HCC cells.Genes & genomics · 2026Article
- The Protein Phosphatase Inhibitor LB100 Targets the Mesenchymal Lineage of Pancreatic Ductal Adenocarcinoma.MedComm · 2026Article
- G0 or no-G0: phosphatase control of quiescence and cell cycle entry.Biochemical Society transactions · 2026Review
- Adulthood depletion of Integrator extends lifespan and healthspan via defective pre-mRNA processing.bioRxiv : the preprint server for biology · 2026Article
- Lactylation-Driven YTHDC1 Alleviates MASLD by Suppressing PTPN22-Mediated Dephosphorylation of NLRP3.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Integrator 20th anniversary: a molecular machine indispensable in development and disease.Trends in molecular medicine · 2026Review
- Protein phosphatase 2A orchestrates hematopoietic fate determination via modulation of lactate metabolism.Haematologica · 2026Article
- Small Molecule Activator of Phosphatase PP2A Remodels Scaffold PR65 Structural Dynamics To Promote Holoenzyme Assembly.JACS Au · 2026Article
- PP2A activation targets MYCN in neuroblastoma.Cell death & disease · 2026Article
- Nano-PROTACs for precision medicine: engineering strategies for enhanced targeting and potency.Journal of nanobiotechnology · 2026Review
- Transcriptional condensates enrich phosphorylated PRMT2 to stimulate H3R8me2a deposition and hypoxic response in glioblastoma.Science China. Life sciences · 2026Article
- Article
58 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
33 authors at 6 institutions in 3 countries.
Stephin J VervoortPeter MacCallum Cancer Centre, Melbourne 3000, VIC, Australia; The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville 3010, VIC, Australia. Electronic address: stephin.vervoort@petermac.org.
Sarah A WelshThe Wistar Institute, Philadelphia, PA 19104, USA; Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Jennifer R DevlinPeter MacCallum Cancer Centre, Melbourne 3000, VIC, Australia; The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville 3010, VIC, Australia.
Elisa BarbieriThe Wistar Institute, Philadelphia, PA 19104, USA.
Deborah A KnightPeter MacCallum Cancer Centre, Melbourne 3000, VIC, Australia; The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville 3010, VIC, Australia.
Sarah OffleyThe Wistar Institute, Philadelphia, PA 19104, USA; Cell and Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Stefan BjelosevicPeter MacCallum Cancer Centre, Melbourne 3000, VIC, Australia; The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville 3010, VIC, Australia.
Matteo CostacurtaPeter MacCallum Cancer Centre, Melbourne 3000, VIC, Australia; The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville 3010, VIC, Australia.
Izabela TodorovskiPeter MacCallum Cancer Centre, Melbourne 3000, VIC, Australia; The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville 3010, VIC, Australia.
Conor J KearneyPeter MacCallum Cancer Centre, Melbourne 3000, VIC, Australia; The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville 3010, VIC, Australia.
Jarrod J SandowThe Walter and Eliza Hall Institute, Parkville 3010, VIC, Australia; Department of Medical Biology, University of Melbourne, Parkville 3010, VIC, Australia.
Zheng FanPeter MacCallum Cancer Centre, Melbourne 3000, VIC, Australia; The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville 3010, VIC, Australia.
Benjamin BlythPeter MacCallum Cancer Centre, Melbourne 3000, VIC, Australia.
Victoria McLeodPeter MacCallum Cancer Centre, Melbourne 3000, VIC, Australia.
Joseph H A VissersPeter MacCallum Cancer Centre, Melbourne 3000, VIC, Australia; The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville 3010, VIC, Australia; Centre for Cancer Research and Department of Clinical Pathology, University of Melbourne, Parkville 3010, VIC, Australia.
Karolina PavicTurku Bioscience Centre, University of Turku and Åbo Akademi University, Turku FI-20014, Finland; Institute of Biomedicine, University of Turku, Turku FI-20014, Finland.
Ben P MartinPeter MacCallum Cancer Centre, Melbourne 3000, VIC, Australia; The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville 3010, VIC, Australia.
Gareth GregoryPeter MacCallum Cancer Centre, Melbourne 3000, VIC, Australia; The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville 3010, VIC, Australia; School of Clinical Sciences at Monash Health, Monash University, Clayton 3168, VIC, Australia.
Elena DemosthenousPeter MacCallum Cancer Centre, Melbourne 3000, VIC, Australia.
Magnus ZethovenPeter MacCallum Cancer Centre, Melbourne 3000, VIC, Australia.
Isabella Y KongThe Walter and Eliza Hall Institute, Parkville 3010, VIC, Australia; Department of Medical Biology, University of Melbourne, Parkville 3010, VIC, Australia.
Edwin D HawkinsThe Walter and Eliza Hall Institute, Parkville 3010, VIC, Australia; Department of Medical Biology, University of Melbourne, Parkville 3010, VIC, Australia.
Simon J HoggPeter MacCallum Cancer Centre, Melbourne 3000, VIC, Australia; The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville 3010, VIC, Australia.
Madison J KellyPeter MacCallum Cancer Centre, Melbourne 3000, VIC, Australia; The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville 3010, VIC, Australia.
Andrea NewboldPeter MacCallum Cancer Centre, Melbourne 3000, VIC, Australia; The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville 3010, VIC, Australia.
Kaylene J SimpsonPeter MacCallum Cancer Centre, Melbourne 3000, VIC, Australia.
Otto KaukoTurku Bioscience Centre, University of Turku and Åbo Akademi University, Turku FI-20014, Finland; Institute of Biomedicine, University of Turku, Turku FI-20014, Finland.
Kieran F HarveyPeter MacCallum Cancer Centre, Melbourne 3000, VIC, Australia; The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville 3010, VIC, Australia; Department of Anatomy and Developmental Biology, and Biomedicine Discovery Institute, Monash University, Clayton 3168, VIC, Australia.
Michael OhlmeyerMount Sinai School of Medicine, New York, NY 10029, USA; Atux Iskay LLC, Plainsboro, NJ 08536, USA.
Jukka WestermarckTurku Bioscience Centre, University of Turku and Åbo Akademi University, Turku FI-20014, Finland; Institute of Biomedicine, University of Turku, Turku FI-20014, Finland.
Nathanael GrayDana Farber Cancer Institute, Boston, MA 02215, USA.
Alessandro GardiniThe Wistar Institute, Philadelphia, PA 19104, USA. Electronic address: agardini@wistar.org.
Ricky W JohnstonePeter MacCallum Cancer Centre, Melbourne 3000, VIC, Australia; The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville 3010, VIC, Australia. Electronic address: ricky.johnstone@petermac.org.
The University of Melbourne · AUPeter MacCallum Cancer Centre · AUThe Wistar Institute · USÅbo Akademi University · FIDana-Farber Cancer Institute · USPrinceton Satellite Systems (United States) · US
Funding
Tumor Microenvironment and MetastasisP30CA010815 · NCI · WISTAR INSTITUTE · PI Luis J Montaner · 1985 to 2026
$75.9MTRAINING PROGRAM IN BASIC CANCER RESEARCHT32CA009171 · NCI · WISTAR INSTITUTE · PI Alessandro Gardini · 1985 to 2026
$15.3MPredoctoral Training at the Chemistry-Biology InterfaceT32GM071339 · NIGMS · WISTAR INSTITUTE · PI MARMORSTEIN, RONEN, SPEICHER, DAVID W. · 2005 to 2019
$3.2MRole of an Integrator-EGR axis in the regulation of myeloid enhancers (Admin Supp)R01HL141326 · NHLBI · WISTAR INSTITUTE · PI GARDINI, ALESSANDRO · 2019 to 2023
$2.7MPredoctoral Training at the Chemistry-Biology InterfaceT32GM133398 · NIGMS · UNIVERSITY OF PENNSYLVANIA · PI Ronen Marmorstein, Ernest James Petersson · 2020 to 2026
$2.4MNCI NIH HHS P30 CA010815NCI NIH HHS T32 CA009171NHLBI NIH HHS R01 HL141326NIGMS NIH HHS T32 GM071339NIGMS NIH HHS T32 GM133398
Abstract
Gene expression by RNA polymerase II (RNAPII) is tightly controlled by cyclin-dependent kinases (CDKs) at discrete checkpoints during the transcription cycle. The pausing checkpoint following transcription initiation is primarily controlled by CDK9. We discovered that CDK9-mediated, RNAPII-driven transcription is functionally opposed by a protein phosphatase 2A (PP2A) complex that is recruited to transcription sites by the Integrator complex subunit INTS6. PP2A dynamically antagonizes phosphorylation of key CDK9 substrates including DSIF and RNAPII-CTD. Loss of INTS6 results in resistance to tumor cell death mediated by CDK9 inhibition, decreased turnover of CDK9 phospho-substrates, and amplification of acute oncogenic transcriptional responses. Pharmacological PP2A activation synergizes with CDK9 inhibition to kill both leukemic and solid tumor cells, providing therapeutic benefit in vivo. These data demonstrate that fine control of gene expression relies on the balance between kinase and phosphatase activity throughout the transcription cycle, a process dysregulated in cancer that can be exploited therapeutically.
Indexed as
Molecular Targeted TherapyTranscription, GeneticAnimalsCell Line, TumorCyclin-Dependent Kinase 9Drug Resistance, NeoplasmGene Expression Regulation, NeoplasticHumansMiceMice, Inbred NODNeoplasmsPhosphorylationProtein BindingProtein Phosphatase 2RNA-Binding ProteinsRNA Polymerase IICDK9 protein, humanCyclin-Dependent Kinase 9INTS6 protein, humanProtein Phosphatase 2RNA-Binding ProteinsRNA Polymerase IITumor Suppressor ProteinscancerCDK9CRISPR-Cas9 screenCTDIntegratorpause-releasephosphatasePP2APP2A activationRNA polymerase IItranscriptional elongation
Identifiers
What OpenQuestion holds
Textmetadata
LicenceTDM
Read underepoch 390
Registered trials
None linked
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.