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Mutant p53 drives multinucleation and invasion through a process that is suppressed by ANKRD11

Oncogene volume 31, pages 2836–2848 (2012)Cite this article

Abstract

Mutations of p53 in cancer can result in a gain of function associated with tumour progression and metastasis. We show that inducible expression of several p53 ‘hotspot’ mutants promote a range of centrosome abnormalities, including centrosome amplification, increased centrosome size and loss of cohesion, which lead to mitotic defects and multinucleation. These mutant p53-expressing cells also show a change in morphology and enhanced invasive capabilities. Consequently, we sought for a means to specifically target the function of mutant p53 in cancer cells. This study has identified ANKRD11 as a key regulator of the oncogenic potential of mutant p53. Loss of ANKRD11 expression with p53 mutation defines breast cancer patients with poor prognosis. ANKRD11 alleviates the mitotic defects driven by mutant p53 and suppresses mutant p53-mediated mesenchymal-like transformation and invasion. Mechanistically, we show that ANKRD11 restores a native conformation to the mutant p53 protein and causes dissociation of the mutant p53–p63 complex. This represents the first evidence of an endogenous protein with the capacity to suppress the oncogenic properties of mutant p53.

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Acknowledgements

We thank Vivek Mittal for the ecdysone-inducible constructs; Karen Vousden and Patricia Muller for the p63 and p73 constructs; Maria Lung, Sumitra Deb and Chikashi Ishioka for the mutant p53 constructs; Jeffrey Salisbury for the anti-centrin antibody; Anne-Marie Cleton-Jansen for providing patient material; and Darryl Russell and Kira Height for technical assistance. We acknowledge the Cancer Council of South Australia and San Remo for financial support. KKK is a National Health and Medical Research Council (NHMRC) Senior Principal Research Fellow, and this work is supported by an NHMRC Program grant to KKK. FA is supported by the Cancer Council NSW, the Cure Cancer Foundation Australia and the Cancer Council SA.

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Authors and Affiliations

  1. Cancer Therapeutics Laboratory, Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia

    J E Noll, R Kumar, D F Callen & P M Neilsen

  2. Signal Transduction Laboratory, Queensland Institute of Medical Research, Brisbane, Queensland, Australia

    J Jeffery, F Al-Ejeh & K K Khanna

  3. Sarcoma Research Group, Discipline of Medicine, University of Adelaide & Hanson Institute, Adelaide, South Australia, Australia

    P M Neilsen

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  1. J E Noll
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Noll, J., Jeffery, J., Al-Ejeh, F. et al. Mutant p53 drives multinucleation and invasion through a process that is suppressed by ANKRD11. Oncogene 31, 2836–2848 (2012). https://doi.org/10.1038/onc.2011.456

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