| Skp2 targeting suppresses tumorigenesis by Arf-p53-independent cellular senescence. | |
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MedLine Citation:
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PMID: 20237562 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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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Authors:
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Hui-Kuan Lin; Zhenbang Chen; Guocan Wang; Caterina Nardella; Szu-Wei Lee; Chia-Hsin Chan; Chan-Hsin Chan; Wei-Lei Yang; Jing Wang; Ainara Egia; Keiichi I Nakayama; Carlos Cordon-Cardo; Julie Teruya-Feldstein; Pier Paolo Pandolfi |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. |
Journal Detail:
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Title: Nature Volume: 464 ISSN: 1476-4687 ISO Abbreviation: Nature Publication Date: 2010 Mar |
Date Detail:
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Created Date: 2010-03-18 Completed Date: 2010-04-29 Revised Date: 2012-04-19 |
Medline Journal Info:
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Nlm Unique ID: 0410462 Medline TA: Nature Country: England |
Other Details:
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Languages: eng Pagination: 374-9 Citation Subset: IM |
Affiliation:
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Cancer Biology and Genetics Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Activating Transcription Factor 4
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metabolism Adenovirus E1A Proteins / genetics, metabolism Animals Cell Aging* / drug effects Cell Transformation, Neoplastic* / drug effects Cells, Cultured Cyclin-Dependent Kinase Inhibitor p16 / deficiency, genetics, metabolism Cyclin-Dependent Kinase Inhibitor p21 / metabolism Cyclin-Dependent Kinase Inhibitor p27 / metabolism Fibroblasts Male Mice PTEN Phosphohydrolase / deficiency, genetics, metabolism Prostate / cytology, metabolism Prostatic Neoplasms / drug therapy, pathology, prevention & control Proto-Oncogene Proteins p21(ras) / genetics, metabolism S-Phase Kinase-Associated Proteins / antagonists & inhibitors, genetics, metabolism* SKP Cullin F-Box Protein Ligases / metabolism Tumor Suppressor Protein p53 / deficiency, metabolism |
| Grant Support | |
ID/Acronym/Agency:
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R01 CA082328-13/CA/NCI NIH HHS; R01 CA082328-14/CA/NCI NIH HHS; R01 CA082328-15/CA/NCI NIH HHS; R01 MD004038-03/MD/NIMHD NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Adenovirus E1A Proteins; 0/Atf4 protein, mouse; 0/Cdkn1b protein, mouse; 0/Cdkn2a protein, mouse; 0/Cyclin-Dependent Kinase Inhibitor p16; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/S-Phase Kinase-Associated Proteins; 0/Tumor Suppressor Protein p53; 145891-90-3/Activating Transcription Factor 4; 147604-94-2/Cyclin-Dependent Kinase Inhibitor p27; EC 3.1.3.48/Pten protein, mouse; EC 3.1.3.67/PTEN Phosphohydrolase; EC 3.6.5.2/Proto-Oncogene Proteins p21(ras); EC 6.3.2.19/SKP Cullin F-Box Protein Ligases |
| Comments/Corrections | |
Comment In:
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Nature. 2010 Mar 18;464(7287):363-4
[PMID:
20237557
]
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Erratum In:
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Nature. 2010 Jul 15;466(7304):398 Note: Chan, Chan-Hsin [corrected to Chan, Chia-Hsin] |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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