Publication Date:
2010-03-20
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2928066/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2928066/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lin, Hui-Kuan -- Chen, Zhenbang -- Wang, Guocan -- Nardella, Caterina -- Lee, Szu-Wei -- Chan, Chia-Hsin -- Yang, Wei-Lei -- Wang, Jing -- Egia, Ainara -- Nakayama, Keiichi I -- Cordon-Cardo, Carlos -- Teruya-Feldstein, Julie -- Pandolfi, Pier Paolo -- R01 CA082328/CA/NCI NIH HHS/ -- R01 CA082328-13/CA/NCI NIH HHS/ -- R01 MD004038/MD/NIMHD NIH HHS/ -- England -- Nature. 2010 Mar 18;464(7287):374-9. doi: 10.1038/nature08815.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Biology and Genetics Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20237562" target="_blank"〉PubMed〈/a〉
Keywords:
Activating Transcription Factor 4/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
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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