Rb Regulates DNA Damage Response and Cellular Senescence through E2F-Dependent Suppression of N-Ras Isoprenylation
Open accessAbstract
Oncogene-induced cellular senescence is well documented, but little is known about how infinite cell proliferation induced by loss of tumor suppressor genes is antagonized by cellular functions. Rb heterozygous mice generate Rb-deficient C cell adenomas that progress to adenocarcinomas following biallelic loss of N-ras. Here, we demonstrate that pRb inactivation induces aberrant expression of farnesyl diphosphate synthase, many prenyltransferases, and their upstream regulators sterol regulatory element-binding proteins (SREBPs) in an E2F-dependent manner, leading to enhanced isoprenylation and activation of N-Ras. Consequently, elevated N-Ras activity induces DNA damage response and p130-dependent cellular senescence in Rb-deficient cells. Furthermore, Rb heterozygous mice additionally lacking any of Ink4a, Arf, or Suv39h1 generated C cell adenocarcinomas, suggesting that cellular senescence antagonizes Rb-deficient carcinogenesis.
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Loss of tumour suppressors PTEN, RB, NF1, and INPP4B is associated with senescence in premalignant tumours.
“The loss of tumour suppressors, such as PTEN 23 (BOX 2), RB 27 , neurofribromin 1 (NF1) 28 and inositol polyphosphate-4-phosphatase, type II (INPP4B) 29 , has also been associated with senescence in premalignant tumours.”
From Inside and out: the activities of senescence in cancer (2014) · cites this paper as [27]
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- Authors
- Shamma, A., Takegami, Y., Miki, T., Kitajima, S., Noda, M., Obara, T., Okamoto, T., & Takahashi, C.
- Affiliations
- Kyoto University (JP)
- Tokyo Women's Medical University (JP)
- Corresponding author
- Takahashi, Chiaki
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2009-04
- Volume
- 15
- Issue
- 4
- Pages
- 255-269
- ISSN
- 1535-6108 (ISSN-L)
- OpenAlex
- W2122846804
- Cited by
- 140
- References
- 63
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 8 · 2023: 5 · 2022: 6 · 2021: 14 · 2020: 10 · 2019: 12 · 2018: 5 · 2017: 7 · 2016: 10 · 2015: 11 · 2014: 11 · 2013: 9 · 2012: 7
- FWCI
- 5.96
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Institutional Repositories DataBase (IRDB) (submittedVersion)
- Institutional Repositories DataBase (IRDB) (submittedVersion, cc-by-nc-nd)
- Kanazawa University Repository for Academic Resources (DSpace) (Kanazawa University) (submittedVersion, cc-by-nc-nd)
- Kyoto University Research Information Repository (Kyoto University) (submittedVersion)
- Funders
- Princess Takamatsu Cancer Research Fund
- Takeda Science Foundation
- Ministry of Education, Culture, Sports, Science and Technology
- 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 › Protein Kinase Regulation and GTPase Signaling
- Keywords
- retinoblastoma protein, oncogene-induced senescence, NRAS, isoprenylation, DNA damage response, E2F transcription factors, farnesyl diphosphate synthase, prenyltransferase, SREBP, p130, INK4A, ARF, SUV39H1, tumor suppressor inactivation, carcinogenesis
- MeSH terms
- Adenocarcinoma, Adenoma, Animals, Cell Membrane, DNA Damage, DNA Repair, Humans, Immunoenzyme Techniques, Genes, ras, Thyroid Neoplasms, Retinoblastoma Protein, Cellular Senescence, Protein Prenylation, Mice, Knockout, Cyclin-Dependent Kinase Inhibitor p16, Brain Stem Neoplasms, Protein Transport, Chromatin Immunoprecipitation, E2F Transcription Factors, Mice, Prenylation
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