ArticleMolecular cell2021
NR4A1 regulates expression of immediate early genes, suppressing replication stress in cancer.
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Article in Molecular cell, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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46 citing papers in PubMed, 67 citations in OpenAlex.
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- Controversy and multiple roles of the solitary nucleus receptor Nur77 in disease and physiology.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2025Review
- A Novel Molecular Profile of Hormone-Sensitive Prostate Cancer Defines High Risk Patients.Cancer medicine · 2025Article
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Authors and funding
28 authors at 4 institutions in 1 country.
Hongshan GuoMassachusetts General Hospital Cancer Center, Boston, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
Gabriel GolczerMassachusetts General Hospital Cancer Center, Boston, MA, USA.
Ben S WittnerMassachusetts General Hospital Cancer Center, Boston, MA, USA.
Adam LangenbucherMassachusetts General Hospital Cancer Center, Boston, MA, USA.
Marcus ZachariahMassachusetts General Hospital Cancer Center, Boston, MA, USA.
Taronish D DubashMassachusetts General Hospital Cancer Center, Boston, MA, USA.
Xin HongMassachusetts General Hospital Cancer Center, Boston, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
Valentine ComaillsMassachusetts General Hospital Cancer Center, Boston, MA, USA.
Risa BurrMassachusetts General Hospital Cancer Center, Boston, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
Richard Y EbrightMassachusetts General Hospital Cancer Center, Boston, MA, USA.
Elad HorwitzMassachusetts General Hospital Cancer Center, Boston, MA, USA.
Joanna A VuilleMassachusetts General Hospital Cancer Center, Boston, MA, USA.
Soroush HajizadehMassachusetts General Hospital Cancer Center, Boston, MA, USA.
Devon F WileyMassachusetts General Hospital Cancer Center, Boston, MA, USA.
Brittany A ReevesMassachusetts General Hospital Cancer Center, Boston, MA, USA.
Jia-Min ZhangMassachusetts General Hospital Cancer Center, Boston, MA, USA.
Kira L NiederhofferMassachusetts General Hospital Cancer Center, Boston, MA, USA.
Chenyue LuMassachusetts General Hospital Cancer Center, Boston, MA, USA.
Benjamin WesleyMassachusetts General Hospital Cancer Center, Boston, MA, USA.
Uyen HoMassachusetts General Hospital Cancer Center, Boston, MA, USA.
Linda T NiemanMassachusetts General Hospital Cancer Center, Boston, MA, USA.
Mehmet TonerCenter for Bioengineering in Medicine and Shriners Hospital, Harvard Medical School, Boston, MA 02114, USA; Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Shobha VasudevanMassachusetts General Hospital Cancer Center, Boston, MA, USA; Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Lee ZouMassachusetts General Hospital Cancer Center, Boston, MA, USA; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Raul MostoslavskyMassachusetts General Hospital Cancer Center, Boston, MA, USA; Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Shyamala MaheswaranMassachusetts General Hospital Cancer Center, Boston, MA, USA; Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Electronic address: maheswaran@helix.mgh.harvard.edu.
Michael S LawrenceMassachusetts General Hospital Cancer Center, Boston, MA, USA; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Electronic address: mslawrence@mgh.harvard.edu.
Daniel A HaberMassachusetts General Hospital Cancer Center, Boston, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA; Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Electronic address: dhaber@mgh.harvard.edu.
Massachusetts General Hospital · USHarvard University · USHoward Hughes Medical Institute · USShriners Hospitals for Children - Erie · US
Funding
Point-of care Microfluidics for Early Detection of CancerU01EB012493 · NIBIB · MASSACHUSETTS GENERAL HOSPITAL · PI HABER, DANIEL A., TONER, MEHMET · 2010 to 2018
$19.6MBio-MicroElectroMechanical Systems Resource CenterP41EB002503 · NIBIB · MASSACHUSETTS GENERAL HOSPITAL · PI TONER, MEHMET · 2004 to 2018
$17.4MModeling Metastasis and Acquired Drug Resistance Using Circulating Tumor CellsR01CA129933 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI Daniel A. Haber · 2008 to 2026
$7.5MHigh-flow microfluidics of leukapheresis blood products for functional analysis of breast circulating tumor cellsR01CA255602 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI HABER, DANIEL A., MAHESWARAN, SHYAMALA · 2021 to 2025
$3.2MMetastasis and biophysics of clusters of circulating tumor cells in the microcirculationU01CA214297 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI HABER, DANIEL A., MAHESWARAN, SHYAMALA · 2018 to 2022
$2.9MImplications of the ATR Checkpoint Kinase in Radiation and Targeted TherapiesR01CA197779 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI ZOU, LEE · 2015 to 2020
$2.4MMicrofluidic sorting of lung cancer cells from leukapheresis product as an alternative to metastatic tumor biopsyR01CA260304 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI HABER, DANIEL A., MAHESWARAN, SHYAMALA · 2021 to 2025
$2.2MMIS mediated inhibition of breast cell growthR01CA089138 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI MAHESWARAN, SHYAMALA · 2001 to 2008
$2.1MSpecialized post-transcriptional mechanisms of gene expression in quiescenceR35GM134944 · NIGMS · MASSACHUSETTS GENERAL HOSPITAL · PI VASUDEVAN, SHOBHA · 2020 to 2023
$1.8MThe histone deacetylase SIRT6 modulates Transcriptional pausingR01GM128448 · NIGMS · MASSACHUSETTS GENERAL HOSPITAL · PI MOSTOSLAVSKY, RAUL · 2019 to 2022
$1.6MRole of RNA methylation in chemoresistant cancer cellsR21CA220103 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI VASUDEVAN, SHOBHA · 2020 to 2021
$424kNCI NIH HHS R01 CA089138NCI NIH HHS R01 CA129933NCI NIH HHS R01 CA197779NCI NIH HHS R01 CA255602NCI NIH HHS R01 CA260304NCI NIH HHS R21 CA220103NCI NIH HHS U01 CA214297NIBIB NIH HHS P41 EB002503NIBIB NIH HHS U01 EB012493NIGMS NIH HHS R01 GM128448NIGMS NIH HHS R35 GM134944
Abstract
Deregulation of oncogenic signals in cancer triggers replication stress. Immediate early genes (IEGs) are rapidly and transiently expressed following stressful signals, contributing to an integrated response. Here, we find that the orphan nuclear receptor NR4A1 localizes across the gene body and 3' UTR of IEGs, where it inhibits transcriptional elongation by RNA Pol II, generating R-loops and accessible chromatin domains. Acute replication stress causes immediate dissociation of NR4A1 and a burst of transcriptionally poised IEG expression. Ectopic expression of NR4A1 enhances tumorigenesis by breast cancer cells, while its deletion leads to massive chromosomal instability and proliferative failure, driven by deregulated expression of its IEG target, FOS. Approximately half of breast and other primary cancers exhibit accessible chromatin domains at IEG gene bodies, consistent with this stress-regulatory pathway. Cancers that have retained this mechanism in adapting to oncogenic replication stress may be dependent on NR4A1 for their proliferation.
Indexed as
Cell ProliferationMitosis3' Untranslated RegionsAnimalsAntineoplastic AgentsBinding SitesBreast NeoplasmsChromatin Assembly and DisassemblyFemaleGene Expression Regulation, NeoplasticGenomic InstabilityHEK293 CellsHumansImmediate-Early ProteinsIndolesMCF-7 Cells3' Untranslated RegionsAntineoplastic AgentsFOS protein, humanImmediate-Early ProteinsIndolesNR4A1 protein, humanNuclear Receptor Subfamily 4, Group A, Member 1p-carboxymethylphenyl 1,1-bis(3'-indolyl)-1-(p-carboxymethylphenyl)methanePhenylacetatesProto-Oncogene Proteins c-fosRNA Polymerase IIcirculating tumor cellsCTCsgenomic instabilityIEGsimmediate early genesorphan nuclear receptorreplication stressR-loopstranscriptional regulation
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