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TAp63 induces senescence and suppresses tumorigenesis in vivo

Nature Cell Biology volume 11, pages 1451–1457 (2009)Cite this article

Abstract

p63 is distinct from its homologue p53 in that its role as a tumour suppressor is controversial, an issue complicated by the existence of two classes of p63 isoforms1. Here we show that TAp63 isoforms are robust mediators of senescence that inhibit tumorigenesis in vivo. Whereas gain of TAp63 induces senescence, loss of p63 enhances sarcoma development in mice lacking p53. Using a new TAp63-specific conditional mouse model, we demonstrate that TAp63 isoforms are essential for Ras-induced senescence, and that TAp63 deficiency increases proliferation and enhances Ras-mediated oncogenesis in the context of p53 deficiency in vivo. TAp63 induces senescence independently of p53, p19Arf and p16Ink4a, but requires p21Waf/Cip1 and Rb. TAp63-mediated senescence overrides Ras-driven transformation of p53-deficient cells, preventing tumour initiation, and doxycycline-regulated expression of TAp63 activates p21Waf/Cip1, induces senescence and inhibits progression of established tumours in vivo. Our findings demonstrate that TAp63 isoforms function as tumour suppressors by regulating senescence through p53-independent pathways. The ability of TAp63 to trigger senescence and halt tumorigenesis irrespective of p53 status identifies TAp63 as a potential target of anti-cancer therapy for human malignancies with compromised p53.

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Figure 1: TAp63 isoforms mediate senescence in mouse and human cells.
Figure 2: p63 deficiency compromises Ras-induced senescence and enhances sarcoma development in vivo.
Figure 3: TAp63 deficiency compromises Ras-induced senescence, enhances proliferation and increases tumorigenesis.
Figure 4: TAp63 blocks Ras-driven transformation and tumour formation of p53−/− cells in vivo.
Figure 5: Regulated expression of TAp63γ induces senescence and halts tumour progression in vivo.

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References

  1. Yang, A. et al. p63, a p53 homolog at 3q27–29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities. Mol. Cell 2, 305–316 (1998).

    Article  CAS  Google Scholar 

  2. Wu, G. et al. ΔNp63α and TAp63α regulate transcription of genes with distinct biological functions in cancer and development. Cancer Res. 63, 2351–2357 (2003).

    CAS  PubMed  Google Scholar 

  3. Hibi, K. et al. AIS is an oncogene amplified in squamous cell carcinoma. Proc. Natl Acad. Sci. USA 97, 5462–5467 (2000).

    Article  CAS  Google Scholar 

  4. Patturajan, M. et al. ΔNp63 induces β-catenin nuclear accumulation and signaling. Cancer Cell 1, 369–379 (2002).

    Article  CAS  Google Scholar 

  5. Rocco, J. W., Leong, C. O., Kuperwasser, N., DeYoung, M. P. & Ellisen, L. W. p63 mediates survival in squamous cell carcinoma by suppression of p73-dependent apoptosis. Cancer Cell 9, 45–56 (2006).

    Article  CAS  Google Scholar 

  6. Gressner, O. et al. TAp63α induces apoptosis by activating signaling via death receptors and mitochondria. EMBO J. 24, 2458–2471 (2005).

    Article  CAS  Google Scholar 

  7. Suh, E. K. et al. p63 protects the female germ line during meiotic arrest. Nature 444, 624–628 (2006).

    Article  CAS  Google Scholar 

  8. Gallegos, J. R. et al. SCF TrCP1 activates and ubiquitylates TAp63γ. J. Biol. Chem. 283, 66–75 (2008).

    Article  CAS  Google Scholar 

  9. Narita, M. & Lowe, S. W. Senescence comes of age. Nature Med. 11, 920–922 (2005).

    Article  CAS  Google Scholar 

  10. 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 

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

    Article  CAS  Google Scholar 

  12. Keyes, W. M. et al. p63 deficiency activates a program of cellular senescence and leads to accelerated aging. Genes Dev. 19, 1986–1999 (2005).

    Article  CAS  Google Scholar 

  13. Quelle, D. E., Zindy, F., Ashmun, R. A. & Sherr, C. J. Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest. Cell 83, 993–1000 (1995).

    Article  CAS  Google Scholar 

  14. 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 

  15. Mills, A. A. et al. p63 is a p53 homologue required for limb and epidermal morphogenesis. Nature 398, 708–713 (1999).

    Article  CAS  Google Scholar 

  16. Keyes, W. M. et al. p63 heterozygous mutant mice are not prone to spontaneous or chemically induced tumors. Proc. Natl Acad. Sci. USA 103, 8435–8440 (2006).

    Article  CAS  Google Scholar 

  17. Lee, C. H. et al. Gene expression profiling identifies p63 as a diagnostic marker for giant cell tumor of the bone. Mod. Pathol. 21, 531–539 (2008).

    Article  CAS  Google Scholar 

  18. Zheng, B., Mills, A. A. & Bradley, A. A system for rapid generation of coat color-tagged knockouts and defined chromosomal rearrangements in mice. Nucleic Acids Res. 27, 2354–2360 (1999).

    Article  CAS  Google Scholar 

  19. Serber, Z. et al. A C-terminal inhibitory domain controls the activity of p63 by an intramolecular mechanism. Mol. Cell Biol. 22, 8601–8611 (2002).

    Article  CAS  Google Scholar 

  20. Tanaka, N. et al. Cellular commitment to oncogene-induced transformation or apoptosis is dependent on the transcription factor IRF-1. Cell 77, 829–839 (1994).

    Article  CAS  Google Scholar 

  21. Ferbeyre, G. et al. Oncogenic ras and p53 cooperate to induce cellular senescence. Mol. Cell Biol. 22, 3497–3508 (2002).

    Article  CAS  Google Scholar 

  22. Liefer, K. M. et al. Down-regulation of p63 is required for epidermal UV-B-induced apoptosis. Cancer Res. 60, 4016–4020 (2000).

    CAS  PubMed  Google Scholar 

  23. Westfall, M. D., Mays, D. J., Sniezek, J. C. & Pietenpol, J. A. The ΔNp63 α phosphoprotein binds the p21 and 14-3-3 σ promoters in vivo and has transcriptional repressor activity that is reduced by Hay-Wells syndrome-derived mutations. Mol. Cell Biol. 23, 2264–2276 (2003).

    Article  CAS  Google Scholar 

  24. Su, X. et al. TAp63 prevents premature aging by promoting adult stem cell maintenance. Cell Stem Cell 5, 64–75 (2009).

    Article  CAS  Google Scholar 

  25. Hollstein, M., Sidransky, D., Vogelstein, B. & Harris, C. C. p53 mutations in human cancers. Science 253, 49–53 (1991).

    Article  CAS  Google Scholar 

  26. Sherr, C. J. & McCormick, F. The RB and p53 pathways in cancer. Cancer Cell 2, 103–112 (2002).

    Article  CAS  Google Scholar 

  27. Osada, M. et al. Cloning and functional analysis of human p51, which structurally and functionally resembles p53. Nature Med. 4, 839–843 (1998).

    Article  CAS  Google Scholar 

  28. Sunahara, M. et al. Mutational analysis of p51A/TAp63γ, a p53 homolog, in non-small cell lung cancer and breast cancer. Oncogene 18, 3761–3765 (1999).

    Article  CAS  Google Scholar 

  29. Moll, U. M. & Slade, N. p63 and p73: roles in development and tumor formation. Mol. Cancer Res. 2, 371–386 (2004).

    CAS  PubMed  Google Scholar 

  30. MacPartlin, M., Zeng, S. X. & Lu, H. Phosphorylation and stabilization of TAp63γ by IkappaB kinase-β. J. Biol. Chem. 283, 15754–15761 (2008).

    Article  CAS  Google Scholar 

  31. Bergamaschi, D. et al. iASPP oncoprotein is a key inhibitor of p53 conserved from worm to human. Nature Genet. 33, 162–167 (2003).

    Article  CAS  Google Scholar 

  32. Robinson, R. A., Lu, X., Jones, E. Y. & Siebold, C. Biochemical and structural studies of ASPP proteins reveal differential binding to p53, p63, and p73. Structure 16, 259–268 (2008).

    Article  CAS  Google Scholar 

  33. Bell, H. S. et al. A p53-derived apoptotic peptide derepresses p73 to cause tumor regression in vivo. J. Clin. Invest. 117, 1008–1018 (2007).

    Article  CAS  Google Scholar 

  34. Dickins, R. A. et al. Probing tumor phenotypes using stable and regulated synthetic microRNA precursors. Nature Genet. 37, 1289–1295 (2005).

    Article  CAS  Google Scholar 

  35. Dimri, G. P. et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc. Natl Acad. Sci. USA 92, 9363–9367 (1995).

    Article  CAS  Google Scholar 

  36. Bagchi, A. et al. CHD5 is a tumor suppressor at human 1p36. Cell 128, 459–475 (2007).

    Article  CAS  Google Scholar 

  37. Wells, J., Boyd, K. E., Fry, C. J., Bartley, S. M. & Farnham, P. J. Target gene specificity of E2F and pocket protein family members in living cells. Mol. Cell Biol. 20, 5797–5807 (2000).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank D. Burgess, A. Bric, R. Dickins, P. Moody and L. Rodgers for suggestions, and L. Bianco and staff for assistance. A.A.M. and X.G. were supported by an American Cancer Society Research Scholar Award.

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Author notes

  1. William M. Keyes

    Present address: Current address: Centre for Genomic Regulation (CRG), Carrer del Dr. Aiguader, 88, 08003, Barcelona, Spain.,

  2. Cristian Papazoglu

    Present address: Current address: OSI Pharmaceuticals, Inc., 41 Pinelawn Road, Melville, NY 11747, USA.,

Authors and Affiliations

  1. Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, 11724, NY, USA

    Xuecui Guo, William M. Keyes, Cristian Papazoglu, Johannes Zuber, Wangzhi Li, Scott W. Lowe & Alea A. Mills

  2. Howard Hughes Medical Institute, 1 Bungtown Road, Cold Spring Harbor, 11724, NY, USA

    Scott W. Lowe

  3. Department of Pathology, Stanford University, Stanford, 84305, CA, USA

    Hannes Vogel

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Contributions

X.G. and A.A.M. designed and performed experiments, analysed data and prepared the manuscript. W.M.K. performed BrdU immunohistochemistry and immunofluorescent staining; C.P. and W.L. performed western blotting analyses; H.V. performed histopathology; J.Z. and S.W.L. designed and constructed the Tet-on system, which formed the basis of the TAp63-specific inducible expression system.

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Correspondence to Alea A. Mills.

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Guo, X., Keyes, W., Papazoglu, C. et al. TAp63 induces senescence and suppresses tumorigenesis in vivo. Nat Cell Biol 11, 1451–1457 (2009). https://doi.org/10.1038/ncb1988

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