Dose-dependent oncogene-induced senescence in vivo and its evasion during mammary tumorigenesis
Abstract
Activating Ras mutations can induce either proliferation or senescence depending on the cellular context. To determine whether Ras activation has context-dependent effects in the mammary gland, we generated doxycycline-inducible transgenic mice that permit Ras activation to be titrated. Low levels of Ras activation - similar to those found in non-transformed mouse tissues expressing endogenous oncogenic Kras2 - stimulate cellular proliferation and mammary epithelial hyperplasias. In contrast, high levels of Ras activation - similar to those found in tumours bearing endogenous Kras2 mutations - induce cellular senescence that is Ink4a-Arf- dependent and irreversible following Ras downregulation. Chronic low-level Ras induction results in tumour formation, but only after the spontaneous upregulation of activated Ras and evasion of senescence checkpoints. Thus, high-level, but not low-level, Ras activation activates tumour suppressor pathways and triggers an irreversible senescent growth arrest in vivo. We suggest a three-stage model for Ras-induced tumorigenesis consisting of an initial activating Ras mutation, overexpression of the activated Ras allele and, finally, evasion of p53-Ink4a-Arf-dependent senescence checkpoints.
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Several key oncogenes, including ras, cyclin E, raf, and E2F3, are linked to senescence induction and may have a tumour suppressive role.
“Several key oncogenes, including ras, cyclin E, raf, and E2F3 expression, are linked to senescence induction and may have a tumour suppressive role [28,29,30].”
From Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies (2020) · cites this paper as [28]
Senescence is a key mechanism of tumour suppression.
“Senescence is a key mechanism of tumour suppression.”
From Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies (2020) · cites this paper as [28]
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- Authors
- Sarkisian, C. J., Keister, B. A., Stairs, D. B., Boxer, R. B., Moody, S. E., & Chodosh, L. A.
- Affiliations
- University of Pennsylvania (US)
- Corresponding author
- Chodosh, Lewis A.
- Venue
- Nature Cell Biology
- Published
- 2007-04-22
- Volume
- 9
- Issue
- 5
- Pages
- 493-505
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- OpenAlex
- W1998767677
- Semantic Scholar
- 81aa064a3d9f0598d5968cfad02bc31b5d00f511
- Cited by
- 490
- References
- 9
- Citations by year
- 2026: 5 · 2025: 16 · 2024: 26 · 2023: 24 · 2022: 20 · 2021: 21 · 2020: 22 · 2019: 21 · 2018: 20 · 2017: 18 · 2016: 17 · 2015: 25 · 2014: 36 · 2013: 27 · 2012: 33
- FWCI
- 26.26
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Susan G. Komen for the Cure
- University of Pennsylvania
- Susan G. Komen
- National Cancer Institute (CA-92910, CA105490, CA93719, CA98371, U01CA105490, R01CA093719, R01CA098371)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- oncogene-induced senescence, Ras activation, KRAS mutation, mammary carcinogenesis, senescence evasion, Ink4a/Arf, p53, doxycycline-inducible transgenic mice, tumor suppressor pathways, mammary gland
- MeSH terms
- Animals, Cell Transformation, Neoplastic, Dose-Response Relationship, Drug, Doxycycline, Epithelial Cells, Female, Hyperplasia, Mammary Glands, Animal, Mammary Neoplasms, Experimental, Mice, Transgenic, Mutation, Precancerous Conditions, Promoter Regions, Genetic, Receptors, Estrogen, Receptors, Progesterone, Time Factors, Signal Transduction, Oncogene Protein p21(ras), Up-Regulation, Gene Expression Regulation, Neoplastic, Tumor Suppressor Protein p53, Cellular Senescence, Cell Cycle Proteins, Cyclin-Dependent Kinase Inhibitor p16, ADP-Ribosylation Factors, Protein Transport, Cell Proliferation, Mice
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