Senescence bypass screen identifies TBX2, which represses Cdkn2a (p19ARF) and is amplified in a subset of human breast cancers
Abstract
To identify new immortalizing genes with potential roles in tumorigenesis, we performed a genetic screen aimed to bypass the rapid and tight senescence arrest of primary fibroblasts deficient for the oncogene Bmi1. We identified the T-box member TBX2 as a potent immortalizing gene that acts by downregulating Cdkn2a (p19(ARF)). TBX2 represses the Cdkn2a (p19(ARF)) promoter and attenuates E2F1, Myc or HRAS-mediated induction of Cdkn2a (p19(ARF)). We found TBX2 to be amplified in a subset of primary human breast cancers, indicating that it might contribute to breast cancer development.
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Retracted
- Authors
- Jacobs, J. J. L., Keblusek, P., Robanus-Maandag, E., Kristel, P., Lingbeek, M., Nederlof, P. M., van Welsem, T., van de Vijver, M. J., Koh, E. Y., Daley, G. Q., & van Lohuizen, M.
- Affiliations
- The Netherlands Cancer Institute (NL)
- Whitehead Institute for Biomedical Research (US)
- Venue
- Nature Genetics
- Published
- 2000-11
- Volume
- 26
- Issue
- 3
- Pages
- 291-299
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W1548932088
- Cited by
- 368
- References
- 10
- Citations by year
- 2025: 6 · 2024: 1 · 2023: 6 · 2022: 9 · 2021: 14 · 2020: 7 · 2019: 14 · 2018: 13 · 2017: 6 · 2016: 11 · 2015: 8 · 2014: 17 · 2013: 21 · 2012: 11
- FWCI
- 15.25
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- National Institutes of Health (5r29ca076418-04)
- National Cancer Institute (CA76418-01)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- TBX2, senescence bypass, cellular senescence, CDKN2A, BMI1, E2F1, c-Myc, HRAS, gene amplification, breast cancer, fibroblasts
- MeSH terms
- Adenocarcinoma, Animals, Breast Neoplasms, Carrier Proteins, Cell Transformation, Neoplastic, Cells, Cultured, Chromosomes, Human, Pair 17, DNA-Binding Proteins, Female, Fibroblasts, Gene Amplification, Humans, Neoplasm Proteins, Neoplastic Syndromes, Hereditary, Nuclear Proteins, Oncogenes, Promoter Regions, Genetic, Proteins, Proto-Oncogene Proteins, Repressor Proteins, Transcription Factors, Transfection, Protein Biosynthesis, Tumor Cells, Cultured, Gene Expression Regulation, Neoplastic, Proto-Oncogene Proteins c-myc, Proto-Oncogene Proteins p21(ras), Cellular Senescence, Gene Deletion, Cell Cycle Proteins, Genes, BRCA1, COS Cells, Cyclin-Dependent Kinase Inhibitor p16, T-Box Domain Proteins, Tumor Suppressor Protein p14ARF, Transcription Factor DP1, E2F Transcription Factors, E2F1 Transcription Factor, Mice, Retinoblastoma-Binding Protein 1, Polycomb Repressive Complex 1
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