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Skp2 targeting suppresses tumorigenesis by Arf-p53-independent cellular senescence

Nature volume 464, pages 374–379 (2010)Cite this article

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A Corrigendum to this article was published on 15 July 2010

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 p19Arf–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.

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Figure 1: Skp2 loss triggers a new senescence response in MEFs in the context of Pten inactivation and Arf deficiency by a p19 Arf –p53-independent pathway.
Figure 2: Upregulation of p27, p21 and Atf4 drives cellular senescence in Pten+/- Skp2-/- and Arf-/- Skp2-/- MEFs.
Figure 3: Skp2 deficiency restricts tumorigenesis after Pten inactivation by inducing cellular senescence in vivo.
Figure 4: Skp2 inactivation restricts tumorigenesis upon Arf deficiency.
Figure 5: Skp2 deficiency restricts prostate cancer development by triggering cellular senescence in vivo.

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References

  1. Sharpless, N. E. & DePinho, R. A. Cancer: crime and punishment. Nature 436, 636–637 (2005)

    Article  ADS  CAS  Google Scholar 

  2. Chen, Z. et al. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 436, 725–730 (2005)

    Article  ADS  CAS  Google Scholar 

  3. Xue, W. et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445, 656–660 (2007)

    Article  CAS  Google Scholar 

  4. Ventura, A. et al. Restoration of p53 function leads to tumour regression in vivo. Nature 445, 661–665 (2007)

    Article  CAS  Google Scholar 

  5. Braig, M. et al. Oncogene-induced senescence as an initial barrier in lymphoma development. Nature 436, 660–665 (2005)

    Article  ADS  CAS  Google Scholar 

  6. Michaloglou, C. et al. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 436, 720–724 (2005)

    Article  ADS  CAS  Google Scholar 

  7. Collado, M. et al. Tumour biology: senescence in premalignant tumours. Nature 436, 642 (2005)

    Article  ADS  CAS  Google Scholar 

  8. Cantley, L. C. & Neel, B. G. New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc. Natl Acad. Sci. USA 96, 4240–4245 (1999)

    Article  ADS  CAS  Google Scholar 

  9. Di Cristofano, A. & Pandolfi, P. P. The multiple roles of PTEN in tumor suppression. Cell 100, 387–390 (2000)

    Article  CAS  Google Scholar 

  10. Salmena, L., Carracedo, A. & Pandolfi, P. P. Tenets of PTEN tumor suppression. Cell 133, 403–414 (2008)

    Article  CAS  Google Scholar 

  11. Bloom, J. & Pagano, M. Deregulated degradation of the cdk inhibitor p27 and malignant transformation. Semin. Cancer Biol. 13, 41–47 (2003)

    Article  CAS  Google Scholar 

  12. Nakayama, K. I. & Nakayama, K. Regulation of the cell cycle by SCF-type ubiquitin ligases. Semin. Cell Dev. Biol. 16, 323–333 (2005)

    Article  CAS  Google Scholar 

  13. Gstaiger, M. et al. Skp2 is oncogenic and overexpressed in human cancers. Proc. Natl Acad. Sci. USA 98, 5043–5048 (2001)

    Article  ADS  CAS  Google Scholar 

  14. Latres, E. et al. Role of the F-box protein Skp2 in lymphomagenesis. Proc. Natl Acad. Sci. USA 98, 2515–2520 (2001)

    Article  ADS  CAS  Google Scholar 

  15. Shim, E. H. et al. Expression of the F-box protein SKP2 induces hyperplasia, dysplasia, and low-grade carcinoma in the mouse prostate. Cancer Res. 63, 1583–1588 (2003)

    CAS  PubMed  Google Scholar 

  16. Lin, H. K. et al. Phosphorylation-dependent regulation of cytosolic localization and oncogenic function of Skp2 by Akt/PKB. Nature Cell Biol. 11, 420–432 (2009)

    Article  ADS  CAS  Google Scholar 

  17. Chiarle, R. et al. 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. 160, 1457–1466 (2002)

    Article  CAS  Google Scholar 

  18. Nakayama, K. et al. Targeted disruption of Skp2 results in accumulation of cyclin E and p27Kip1, polyploidy and centrosome overduplication. EMBO J. 19, 2069–2081 (2000)

    Article  CAS  Google Scholar 

  19. Lin, A. W. et al. Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling. Genes Dev. 12, 3008–3019 (1998)

    Article  CAS  Google Scholar 

  20. Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D. & Lowe, S. W. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88, 593–602 (1997)

    Article  CAS  Google Scholar 

  21. Kim, W. Y. & Sharpless, N. E. The regulation of INK4/ARF in cancer and aging. Cell 127, 265–275 (2006)

    Article  CAS  Google Scholar 

  22. Yaswen, P. & Campisi, J. Oncogene-induced senescence pathways weave an intricate tapestry. Cell 128, 233–234 (2007)

    Article  CAS  Google Scholar 

  23. Hemann, M. T. et al. An epi-allelic series of p53 hypomorphs created by stable RNAi produces distinct tumor phenotypes in vivo. Nature Genet. 33, 396–400 (2003)

    Article  CAS  Google Scholar 

  24. Gottlieb, E., Haffner, R., von Ruden, T., Wagner, E. F. & Oren, M. Down-regulation of wild-type p53 activity interferes with apoptosis of IL-3-dependent hematopoietic cells following IL-3 withdrawal. EMBO J. 13, 1368–1374 (1994)

    Article  CAS  Google Scholar 

  25. Chen, Z. et al. Differential p53-independent outcomes of p19Arf loss in oncogenesis. Sci. Signal. 2, ra44 (2009)

    PubMed  PubMed Central  Google Scholar 

  26. Bartkova, J. et al. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature 444, 633–637 (2006)

    Article  ADS  CAS  Google Scholar 

  27. Di Micco, R. et al. Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature 444, 638–642 (2006)

    Article  ADS  CAS  Google Scholar 

  28. Mallette, F. A., Gaumont-Leclerc, M. F. & Ferbeyre, G. The DNA damage signaling pathway is a critical mediator of oncogene-induced senescence. Genes Dev. 21, 43–48 (2007)

    Article  CAS  Google Scholar 

  29. Yu, Z. K., Gervais, J. L. & Zhang, H. Human CUL-1 associates with the SKP1/SKP2 complex and regulates p21CIP1/WAF1and cyclin D proteins. Proc. Natl Acad. Sci. USA 95, 11324–11329 (1998)

    Article  ADS  CAS  Google Scholar 

  30. Denoyelle, C. et al. Anti-oncogenic role of the endoplasmic reticulum differentially activated by mutations in the MAPK pathway. Nature Cell Biol. 8, 1053–1063 (2006)

    Article  CAS  Google Scholar 

  31. Kim, I., Xu, W. & Reed, J. C. Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities. Nature Rev. Drug Discov. 7, 1013–1030 (2008)

    Article  CAS  Google Scholar 

  32. Di Cristofano, A. et al. Impaired Fas response and autoimmunity in Pten+/- mice. Science 285, 2122–2125 (1999)

    Article  CAS  Google Scholar 

  33. Di Cristofano, A., Pesce, B., Cordon-Cardo, C. & Pandolfi, P. P. Pten is essential for embryonic development and tumour suppression. Nature Genet. 19, 348–355 (1998)

    Article  CAS  Google Scholar 

  34. Kamijo, T., Bodner, S., van de Kamp, E., Randle, D. H. & Sherr, C. J. Tumor spectrum in ARF-deficient mice. Cancer Res. 59, 2217–2222 (1999)

    CAS  PubMed  Google Scholar 

  35. Kamijo, T. et al. Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19ARF. Cell 91, 649–659 (1997)

    Article  CAS  Google Scholar 

  36. Soucy, T. A. et al. An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer. Nature 458, 732–736 (2009)

    Article  ADS  CAS  Google Scholar 

  37. Young, A. P. et al. VHL loss actuates a HIF-independent senescence programme mediated by Rb and p400. Nature Cell Biol. 10, 361–369 (2008)

    Article  ADS  CAS  Google Scholar 

  38. Kuo, Y. L. & Giam, C. Z. Activation of the anaphase promoting complex by HTLV-1 tax leads to senescence. EMBO J. 25, 1741–1752 (2006)

    Article  CAS  Google Scholar 

  39. Agarwal, A. et al. Absence of SKP2 expression attenuates BCR-ABL-induced myeloproliferative disease. Blood 112, 1960–1970 (2008)

    Article  CAS  Google Scholar 

  40. Lin, H. K., Bergmann, S. & Pandolfi, P. P. Cytoplasmic PML function in TGF-β signalling. Nature 431, 205–211 (2004)

    Article  ADS  CAS  Google Scholar 

  41. Yang, W. L. et al. The E3 ligase TRAF6 regulates Akt ubiquitination and activation. Science 325, 1134–1138 (2009)

    Article  ADS  CAS  Google Scholar 

  42. Chen, Z. et al. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 436, 725–730 (2005)

    Article  ADS  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to C. J. Sherr, S. W. Lowe and M. Oren for mice and reagents. We would also like to thank B. Carver, L. DiSantis, J. Clossey and S. Megan for editing and critical reading of the manuscript, J. A. Koutcher, C. Le, C. Matei and M. Lupa for MRI analysis, as well all the members of the Pandolfi laboratory for comments and discussion. We extend our thanks to M. Rolfe, P. G. Smith, and Millennium Pharmaceuticals for discussion and for providing the MLN4924 compound. This work was supported by NIH grants to P.P.P. and M.D. Anderson Trust Scholar Award and DOD Prostate Cancer New Investigator Award to H.K.L.

Author Contributions H.K.L. and P.P.P. designed the experiments and wrote the manuscript; H.-K.L., Z.C., G.W., S.-W.L., C.N., C.-H.C., W.-L.Y., J.W. and A.E. performed the experiments; C.C.-C. and J.T-F. performed the histopathological analysis of the mice; K.I.N. provided the Skp2-/- mice.

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Author notes

  1. Zhenbang Chen & Carlos Cordon-Cardo

    Present address: Present addresses: Department of Biochemistry and Cancer Biology, Meharry Medical College, 1005 Dr D. B. Todd Jr Boulevard, Nashville, Tennessee 37208-3599, USA (Z.C.); Irving Cancer Research Center, Room 309, 1130 St. Nicholas Avenue, New York, New York 10032, USA (C.C.-C.).,

  2. Guocan Wang, Caterina Nardella and Szu-Wei Lee: These authors contribute equally to this work.

Authors and Affiliations

  1. Cancer Biology and Genetics Program,,

    Hui-Kuan Lin, Zhenbang Chen, Guocan Wang, Caterina Nardella & Pier Paolo Pandolfi

  2. Department of Pathology, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA,

    Hui-Kuan Lin, Zhenbang Chen, Guocan Wang, Caterina Nardella, Carlos Cordon-Cardo, Julie Teruya-Feldstein & Pier Paolo Pandolfi

  3. Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA,

    Hui-Kuan Lin, Szu-Wei Lee, Chan-Hsin Chan, Wei-Lei Yang & Jing Wang

  4. Beth Israel Deaconess Cancer Center and Department of Medicine, Cancer Genetics Program, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA,

    Zhenbang Chen, Guocan Wang, Caterina Nardella, Ainara Egia & Pier Paolo Pandolfi

  5. Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Fukuoka 812-8582, Japan,

    Keiichi I. Nakayama

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Correspondence to Pier Paolo Pandolfi.

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Lin, HK., Chen, Z., Wang, G. et al. Skp2 targeting suppresses tumorigenesis by Arf-p53-independent cellular senescence. Nature 464, 374–379 (2010). https://doi.org/10.1038/nature08815

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