Skp2 targeting suppresses tumorigenesis by Arf-p53-independent cellular senescence
Open accessAbstract
Cellular senescence has been recently shown to have an important role in opposing tumour initiation and promotion. Senescence induced by oncogenes or by loss of tumour suppressor genes is thought to critically depend on induction of the p19(Arf)-p53 pathway. The Skp2 E3-ubiquitin ligase can act as a proto-oncogene and its aberrant overexpression is frequently observed in human cancers. Here we show that although Skp2 inactivation on its own does not induce cellular senescence, aberrant proto-oncogenic signals as well as inactivation of tumour suppressor genes do trigger a potent, tumour-suppressive senescence response in mice and cells devoid of Skp2. Notably, Skp2 inactivation and oncogenic-stress-driven senescence neither elicit activation of the p19(Arf)-p53 pathway nor DNA damage, but instead depend on Atf4, p27 and p21. We further demonstrate that genetic Skp2 inactivation evokes cellular senescence even in oncogenic conditions in which the p19(Arf)-p53 response is impaired, whereas a Skp2-SCF complex inhibitor can trigger cellular senescence in p53/Pten-deficient cells and tumour regression in preclinical studies. Our findings therefore provide proof-of-principle evidence that pharmacological inhibition of Skp2 may represent a general approach for cancer prevention and therapy.
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In Pten loxP/loxP ; Pb-Cre mice, Skp2 ablation restricts prostate cancer.
“| | Pten loxP/loxP ; Pb-Cre | Skp2 ablation | Prostate cancer restriction | 156 | | | |”
From Inside and out: the activities of senescence in cancer (2014) · cites this paper as [156]
Cellular senescence plays beneficial critical roles in numerous biological processes, such as tumor suppression, embryonic tissue remodeling and wound healing after injury.
“Cellular senescence plays beneficial critical roles in numerous biological processes [5], such as tumor suppression [6,7], embryonic tissue remodeling [8] and wound healing after injury [9].”
From Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases (2020) · cites this paper as [6]
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- Authors
- Lin, H.-K., Chen, Z., Wang, G., Nardella, C., Lee, S.-W., Chan, C.-H., Yang, W.-L., Wang, J., Egia, A., Nakayama, K. I., Cordon-Cardo, C., Teruya-Feldstein, J., & Pandolfi, P. P.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Meharry Medical College (US)
- Beth Israel Deaconess Medical Center (US)
- The University of Texas MD Anderson Cancer Center (US)
- Kyushu University (JP)
- Corresponding author
- Pandolfi, Pier Paolo
- Venue
- Nature
- Published
- 2010-03-18
- Volume
- 464
- Issue
- 7287
- Pages
- 374-379
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2928066
- OpenAlex
- W2063864717
- Cited by
- 400
- References
- 42
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 8 · 2023: 14 · 2022: 10 · 2021: 12 · 2020: 26 · 2019: 15 · 2018: 18 · 2017: 29 · 2016: 24 · 2015: 38 · 2014: 33 · 2013: 45 · 2012: 43
- FWCI
- 34.19
- Type
- journal article
- Language
- en
- Update notices
- erratum (2010-07-15)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Institutional Research Information System (Università degli Studi di Trento) (submittedVersion)
- Funders
- U.S. Department of Defense
- National Institutes of Health
- Takeda Oncology
- National Cancer Institute (R01CA082328)
- National Institute on Minority Health and Health Disparities (R01MD004038)
- 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 › Ubiquitin and proteasome pathways
- Keywords
- Skp2, cellular senescence, carcinogenesis, ATF4, p27, p21, oncogenic stress, SCF ubiquitin ligase, tumor suppressor, tumor regression, cancer prevention, cancer therapy, ATF6, cyclin-dependent kinase inhibitors
- MeSH terms
- Proto-Oncogene Mas, Animals, Cell Transformation, Neoplastic, Cells, Cultured, Fibroblasts, Male, Prostate, Prostatic Neoplasms, Tumor Suppressor Protein p53, Proto-Oncogene Proteins p21(ras), Cellular Senescence, Adenovirus E1A Proteins, Cyclin-Dependent Kinase Inhibitor p16, S-Phase Kinase-Associated Proteins, SKP Cullin F-Box Protein Ligases, Cyclin-Dependent Kinase Inhibitor p21, Cyclin-Dependent Kinase Inhibitor p27, PTEN Phosphohydrolase, Mice, Activating Transcription Factor 4
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