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p53-dependent inhibition of mammalian cell survival by a genetically selected peptide aptamer that targets the regulatory subunit of protein kinase CK2

Oncogene volume 25, pages 7343–7353 (2006)Cite this article

Abstract

Based on the perturbation of its expression in human cancers and on its involvement in transformation and tumorigenesis, protein kinase CK2 has recently attracted attention as a potential therapeutic target. To assess the value of CK2 as a target for antiproliferative strategies, we have initiated a program aiming to develop inhibitors targeting specifically the regulatory CK2β subunit. Here, we use a two-hybrid approach to isolate from combinatorial libraries, peptide aptamers that specifically interact with CK2β. One of these (P1), which has significant sequence homology to the cytomegalovirus IE2 protein, binds with high affinity to the N-terminal domain of CK2β without disrupting the formation of the CK2 holoenzyme. Expression of green fluorescent protein (GFP)-P1 in different mammalian cell lines activates p53 phosphorylation on serine 15, induces an upregulation of p21 and the release of the Cyt-C and apoptosis-inducing factor proapoptotic proteins triggering caspase-dependent and caspase-independent apoptosis. GFP-P1-induced apoptosis is associated with a p53-dependent pathway as cell death was abrogated in p53 knocked out cells. In summary, our data show that genetically selected peptide aptamers that specifically target CK2β can induce apoptosis in mammalian cells through the recruitment of a p53-dependent apoptosis pathway. They also emphasize the critical role of CK2β for cell survival and might allow the design of novel proapoptotic agents targeting this protein.

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Acknowledgements

We thank Dr B Ducommun and Dr A Joliot for their generous gift of recombinant Cdc25B and Engrailed proteins, respectively, and B Vogelstein for the WT and p53-null HCT116 cells. Work on CK2 in our group is supported by grants 2004 from the Ligue National contre le Cancer (équipe labellisée), the Institut National de la Santé and the Commissariat à l'Energie Atomique. VM was supported by the Association pour la Recherche sur le Cancer (ARC).

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  1. V Martel and O Filhol: These authors contributed equally to this work.

Authors and Affiliations

  1. Département Réponse et Dynamique Cellulaire, INSERM EMI0104, CEA, Grenoble cedex, France

    V Martel, O Filhol & C Cochet

  2. Aptanomics SA, Lyon, France

    P Colas

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  1. V Martel
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  2. O Filhol
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Correspondence to C Cochet.

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Martel, V., Filhol, O., Colas, P. et al. p53-dependent inhibition of mammalian cell survival by a genetically selected peptide aptamer that targets the regulatory subunit of protein kinase CK2. Oncogene 25, 7343–7353 (2006). https://doi.org/10.1038/sj.onc.1209722

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