Skp2 Targeting Suppresses Tumorigenesis by Arf-p53-independent Cellular Senescence

Overview

Journal Nature

Specialty Science

Date 2010 Mar 19

PMID 20237562

Citations 228

Authors

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

Affiliations

Soon will be listed here.

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)-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.

Citing Articles

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References

Lin H, Bergmann S, Pandolfi P . Cytoplasmic PML function in TGF-beta signalling. Nature. 2004; 431(7005):205-11. DOI: 10.1038/nature02783. View

Di Micco R, Fumagalli M, Cicalese A, Piccinin S, Gasparini P, Luise C . Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature. 2006; 444(7119):638-42. DOI: 10.1038/nature05327. View

Yaswen P, Campisi J . Oncogene-induced senescence pathways weave an intricate tapestry. Cell. 2007; 128(2):233-4. DOI: 10.1016/j.cell.2007.01.005. View

Ventura A, Kirsch D, McLaughlin M, Tuveson D, Grimm J, Lintault L . Restoration of p53 function leads to tumour regression in vivo. Nature. 2007; 445(7128):661-5. DOI: 10.1038/nature05541. View

Xue W, Zender L, Miething C, Dickins R, Hernando E, Krizhanovsky V . Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature. 2007; 445(7128):656-60. PMC: 4601097. DOI: 10.1038/nature05529. View

Young A, Schlisio S, Minamishima Y, Zhang Q, Li L, Grisanzio C . VHL loss actuates a HIF-independent senescence programme mediated by Rb and p400. Nat Cell Biol. 2008; 10(3):361-9. DOI: 10.1038/ncb1699. View

Salmena L, Carracedo A, Pandolfi P . Tenets of PTEN tumor suppression. Cell. 2008; 133(3):403-14. DOI: 10.1016/j.cell.2008.04.013. View

Agarwal A, Bumm T, Corbin A, OHare T, Loriaux M, VanDyke J . Absence of SKP2 expression attenuates BCR-ABL-induced myeloproliferative disease. Blood. 2008; 112(5):1960-70. PMC: 2518897. DOI: 10.1182/blood-2007-09-113860. View

Kim I, Xu W, Reed J . Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities. Nat Rev Drug Discov. 2008; 7(12):1013-30. DOI: 10.1038/nrd2755. View

10.

Lin H, Wang G, Chen Z, Teruya-Feldstein J, Liu Y, Chan C . Phosphorylation-dependent regulation of cytosolic localization and oncogenic function of Skp2 by Akt/PKB. Nat Cell Biol. 2009; 11(4):420-32. PMC: 2830812. DOI: 10.1038/ncb1849. View

11.

Soucy T, Smith P, Milhollen M, Berger A, Gavin J, Adhikari S . An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer. Nature. 2009; 458(7239):732-6. DOI: 10.1038/nature07884. View

12.

Chen Z, Carracedo A, Lin H, Koutcher J, Behrendt N, Egia A . Differential p53-independent outcomes of p19(Arf) loss in oncogenesis. Sci Signal. 2009; 2(84):ra44. PMC: 2928478. DOI: 10.1126/scisignal.2000053. View

13.

Yang W, Wang J, Chan C, Lee S, Campos A, Lamothe B . The E3 ligase TRAF6 regulates Akt ubiquitination and activation. Science. 2009; 325(5944):1134-8. PMC: 3008763. DOI: 10.1126/science.1175065. View

14.

Di Cristofano A, Pandolfi P . The multiple roles of PTEN in tumor suppression. Cell. 2000; 100(4):387-90. DOI: 10.1016/s0092-8674(00)80674-1. View

15.

Nagahama H, Minamishima Y, Matsumoto M, Nakamichi I, Kitagawa K, Shirane M . Targeted disruption of Skp2 results in accumulation of cyclin E and p27(Kip1), polyploidy and centrosome overduplication. EMBO J. 2000; 19(9):2069-81. PMC: 305685. DOI: 10.1093/emboj/19.9.2069. View

16.

Latres E, Chiarle R, Schulman B, Pavletich N, Pellicer A, Inghirami G . Role of the F-box protein Skp2 in lymphomagenesis. Proc Natl Acad Sci U S A. 2001; 98(5):2515-20. PMC: 30169. DOI: 10.1073/pnas.041475098. View

17.

Gstaiger M, Jordan R, Lim M, Catzavelos C, Mestan J, Slingerland J . Skp2 is oncogenic and overexpressed in human cancers. Proc Natl Acad Sci U S A. 2001; 98(9):5043-8. PMC: 33160. DOI: 10.1073/pnas.081474898. View

18.

Chiarle R, Fan Y, Piva R, Boggino H, Skolnik J, Novero D . S-phase kinase-associated protein 2 expression in non-Hodgkin's lymphoma inversely correlates with p27 expression and defines cells in S phase. Am J Pathol. 2002; 160(4):1457-66. PMC: 1867227. DOI: 10.1016/S0002-9440(10)62571-0. View

19.

Bloom J, Pagano M . Deregulated degradation of the cdk inhibitor p27 and malignant transformation. Semin Cancer Biol. 2003; 13(1):41-7. DOI: 10.1016/s1044-579x(02)00098-6. View

20.

Hemann M, Fridman J, Zilfou J, Hernando E, Paddison P, Cordon-Cardo C . An epi-allelic series of p53 hypomorphs created by stable RNAi produces distinct tumor phenotypes in vivo. Nat Genet. 2003; 33(3):396-400. DOI: 10.1038/ng1091. View