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Deregulated E2F Activity Induces Hyperplasia and Senescence-Like Features in the Mouse Pituitary Gland
Open accessAbstract
The retinoblastoma gene, RB1, is one of the most frequently mutated genes in human cancer. Rb heterozygous mice develop pituitary tumors with 100% incidence, and the E2F transcription factors are required for this. To assess whether deregulated E2F activity is sufficient to induce pituitary tumors, we generated transgenic mice expressing an inducible E2F3 protein in the intermediate lobe of the pituitary gland. We found that short-term deregulation of E2F activity, similar to the earliest stages of Rb loss, is able to induce abnormal proliferation of otherwise quiescent melanotrophs. However, while long-term exposure to deregulated E2F activity results in hyperplasia of the intermediate lobe, it did not lead to tumor formation. In fact, melanotrophs become insensitive to sustained E2F stimulation and enter an irreversible senescence-like state. Thus, although deregulated E2F activity results in hyperproliferation, it is not sufficient to mimic loss of Rb, sustain proliferation of melanotrophs, and ultimately induce pituitary tumors. Similarly, we found that primary cells in tissue culture become insensitive to sustained E2F3 activation and undergo premature senescence in a pRB-, p16Ink4a-, and p19Arf-dependent manner. Thus, we conclude that deregulated E2F activity is not sufficient to fully mimic loss of Rb due to the engagement of a senescence response.
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“Studies in various mouse models, supported by correlative evidence from human- derived tissue samples, have underscored the tumour- suppressive role of OIS 81,120-123 .”
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Metadata
- Authors
- Denchi, E. L., Attwooll, C., Pasini, D., & Helin, K.
- Affiliations
- European Institute of Oncology (IT)
- University of Copenhagen (DK)
- Corresponding author
- Helin, Kristian
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2005-04-01
- Volume
- 25
- Issue
- 7
- Pages
- 2660-2672
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC1061636
- OpenAlex
- W2124621255
- Cited by
- 195
- References
- 55
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 2 · 2023: 5 · 2022: 13 · 2021: 8 · 2020: 15 · 2019: 7 · 2018: 4 · 2017: 9 · 2016: 6 · 2015: 4 · 2014: 12 · 2013: 6 · 2012: 11
- FWCI
- 6.69
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed (publishedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- European Commission
- Associazione Italiana per la Ricerca sul Cancro
- Fondazione Italiana per la Ricerca sul Cancro
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- E2F3, retinoblastoma gene, RB1 loss, pituitary tumors, intermediate lobe, melanotrophs, cell proliferation, senescence, premature senescence, p16INK4a, p19ARF, transgenic mice
- MeSH terms
- Aging, Animals, Cells, Cultured, DNA-Binding Proteins, Hyperplasia, Mice, Transgenic, Pituitary Gland, Recombinant Proteins, Transcription Factors, Transcription, Genetic, Cell Cycle Proteins, Cell Proliferation, E2F Transcription Factors, E2F3 Transcription Factor, Mice
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