ArticleProceedings of the National Academy of Sciences of the United States of America2010
Phosphorylation by Cdk2 is required for Myc to repress Ras-induced senescence in cotransformation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 121 papers.
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The trial behind it
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Who cites it
121 citing papers in PubMed, 237 citations in OpenAlex.
- Trial
- MAPK-driven MYC/p21 axis controls senescence bypass and BCL-XL dependence in vincristine-resistant rhabdomyosarcoma.iScience · 2026Article
- Targeting MYC-Driven Cancers: From Oncogenic Addiction to Therapeutic Vulnerability.BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy · 2026Review
- PARK2 Inhibits the progression of colorectal cancer via ubiquitinating MARCKSL1 to inhibit the c-Myc pathway.Cellular and molecular life sciences : CMLS · 2026Article
- CDK2 inhibition promotes neuronal differentiation in neuroblastoma.Scientific reports · 2026Article
- CDK2 inhibitor BLU-222 synergizes with CDK4/6 inhibitors in drug resistant breast cancers through p21/p27 induction.Nature communications · 2026Article
- MYC at the tumor-immune interface: mechanisms of immune escape and immunotherapy resistance.Frontiers in immunology · 2026Review
- G-protein-coupled receptor ADGRG1 drives a protective microglial state in Alzheimer's disease through MYC activation.Neuron · 2025Article
- Targeting c-Myc enhances immunotherapy efficacy in combination with Ras inhibitor in triple-negative breast cancer.Clinical and translational medicine · 2025Article
- The function of MYC in base excision repair protects against RAS-induced senescence.Nucleic acids research · 2025Article
- Mechanistic Roles of Transcriptional Cyclin-Dependent Kinases in Oncogenesis: Implications for Cancer Therapy.Cancers · 2025Review
- TCP1 promotes the progression of malignant tumours by stabilizing c-Myc through the AKT/GSK-3β and ERK signalling pathways.Communications biology · 2025Article
- Targeting senescent stemlike subpopulations in Philadelphia chromosome-like acute lymphoblastic leukemia.Blood · 2025Article
- Targeting CDK2 Confers Vulnerability to Lenvatinib Via Driving Senescence in Anaplastic Thyroid Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Pathological variants in HPV-independent vulvar tumours.Scientific reports · 2025Article
- Exploring the dynamics and interactions of the N-myc transactivation domain through solution nuclear magnetic resonance spectroscopy.The Biochemical journal · 2024Article
- Uncovering Cell Cycle Dysregulations and Associated Mechanisms in Cancer and Neurodegenerative Disorders: A Glimpse of Hope for Repurposed Drugs.Molecular neurobiology · 2024Review
- WDR20 prevents hepatocellular carcinoma senescence by orchestrating the simultaneous USP12/46-mediated deubiquitination of c-Myc.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- MYC and KRAS cooperation: from historical challenges to therapeutic opportunities in cancer.Signal transduction and targeted therapy · 2024Review
- Cellular senescence: Neither irreversible nor reversible.The Journal of experimental medicine · 2024Article
61 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
15 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The MYC and RAS oncogenes are frequently activated in cancer and, together, are sufficient to transform rodent cells. The basis for this cooperativity remains unclear. We found that although Ras interfered with Myc-induced apoptosis, Myc repressed Ras-induced senescence, together abrogating two main barriers of tumorigenesis. Inhibition of cellular senescence required phosphorylation of Myc at Ser-62 by cyclin E/cyclin-dependent kinase (Cdk) 2. Cdk2 interacted with Myc at promoters, where it affected Myc-dependent regulation of genes, including Bmi-1, p16, p21, and hTERT, which encode proteins known to control senescence. Repression of senescence by Myc was abrogated by the Cdk inhibitor p27Kip1, which is induced by antiproliferative signals like IFN-gamma or by pharmacological inhibitors of Cdk2 but not by inhibitors of other Cdks. In contrast, a phospho-mimicking Myc-S62D mutant was resistant to these manipulations. Inhibition of cyclin E/Cdk2 reversed the senescence-associated gene expression pattern imposed by Myc/cyclin E/Cdk2. This indicates a role of Cdk2 as a transcriptional cofactor and activator of the antisenescence function of Myc and provides mechanistic insight into the Myc-p27Kip1 antagonism. Finally, our findings highlight that pharmacological inhibition of Cdk2 activity is a potential therapeutical principle for cancer therapy, in particular for tumors with activated Myc or Ras.
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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.