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Differential protein expression, DNA binding and interaction with SV40 large tumour antigen implicate the p63-family of proteins in replicative senescence

Oncogene volume 21, pages 981–989 (2002)Cite this article

Abstract

P53 activity plays a key role in mammalian cells when they undergo replicative senescence at their Hayflick limit. To determine whether p63 proteins, members of the family of p53-related genes, are also involved in this process, we examined their expression in serially passaged rat embryo fibroblasts. Upon senescence, two truncated ΔNp63 proteins decreased in abundance whereas two TAp63 isoforms accumulated. 2-D gel analysis showed that the ΔNp63 proteins underwent post-translational modifications in both proliferating and senescent cells. Direct binding of ΔNp63 proteins to a p53 consensus motif was greater in proliferating cells than senescent cells. In contrast p63α isoforms bound to DNA in a p53 dependent manner and this was higher in senescent cells than proliferating cells. An interaction of p63α proteins with SV40 large tumour antigen was also detected and ectopic expression of ΔNp63α can extend the lifespan of rat embryo fibroblasts. Taken together the results indicate that p63 proteins may play a role in replicative senescence either by competition for p53 DNA binding sites or by direct interaction with p53 protein bound to DNA.

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Acknowledgements

We are grateful to Hartwig Schmale and Casimir Bamberger for the generous gift of pcDNA3ratKET. We would also like to thank Akunna Akpan, Valentina de Felice and Soren Naaby-Hansen for experimental help. We are indebted to Anita Kobrna, Sandra J Campbell for helpful discussions and Mike O'Hare for help with the manuscript. S Djelloul was initially a fellow of the Association pour la Recherche contre le Cancer. This work was partially funded by financial support to PS Jat from ReNeuron Ltd and to K Barnouin from Kay Kendall Leukaemia Fund.

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Authors and Affiliations

  1. Ludwig Institute for Cancer Research, Royal Free and University College School of Medicine, Courtauld Building, 91 Riding House Street, London, W1W 7BS, UK

    Siham Djelloul, Marina Tarunina, Karin Barnouin & Parmjit S Jat

  2. Department of Biochemistry and Molecular Biology, University College London, Gower Street, London, WC1E 6BT, UK

    Karin Barnouin & Parmjit S Jat

  3. Department of Surgery, LICR-UCL Breast Cancer Laboratory, Royal Free and University College School of Medicine, 67–73 Riding House Street, London, W1P 7LD, UK

    Alan Mackay

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  1. Siham Djelloul
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Correspondence to Parmjit S Jat.

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Djelloul, S., Tarunina, M., Barnouin, K. et al. Differential protein expression, DNA binding and interaction with SV40 large tumour antigen implicate the p63-family of proteins in replicative senescence. Oncogene 21, 981–989 (2002). https://doi.org/10.1038/sj.onc.1205253

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