Skp2 targeting suppresses tumorigenesis by Arf-p53-independent cellular senescence Journal Article
| Authors: | Lin, H.; 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. |
| Article Title: | Skp2 targeting suppresses tumorigenesis by Arf-p53-independent cellular senescence |
| Abstract: | 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 ĝ€"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 p19Arf-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 p19Arf-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. © 2010 Macmillan Publishers Limited. All rights reserved. |
| Keywords: | nonhuman; genetic analysis; animals; mice; dna damage; cells, cultured; mus; proto oncogene; gene expression; protein targeting; tumor regression; protein p53; carcinogenesis; cell transformation, neoplastic; prostatic neoplasms; cancer inhibition; tumor suppressor gene; prostate; dna; protein p27; enzyme inactivation; cyclin-dependent kinase inhibitor p27; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; pten phosphohydrolase; fibroblasts; tumor suppressor protein p53; gene inactivation; protein deficiency; senescence; arf protein; protein p19; cyclin-dependent kinase inhibitor p16; cyclin-dependent kinase inhibitor p21; tumor; protein p21; proto-oncogene proteins p21(ras); cell aging; activating transcription factor 4; disease treatment; s phase kinase associated protein 2; s-phase kinase-associated proteins; skp cullin f-box protein ligases; adenovirus e1a proteins |
| Journal Title: | Nature |
| Volume: | 464 |
| Issue: | 7287 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2010-03-18 |
| Start Page: | 374 |
| End Page: | 379 |
| Language: | English |
| DOI: | 10.1038/nature08815 |
| PUBMED: | 20237562 |
| PROVIDER: | scopus |
| PMCID: | PMC2928066 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 28" - "Export Date: 20 April 2011" - "CODEN: NATUA" - "Source: Scopus" |
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