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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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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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