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p53 is phosphorylated in vitro and in vivo by the delta and epsilon isoforms of casein kinase 1 and enhances the level of casein kinase 1 delta in response to topoisomerase-directed drugs

Abstract

The p53 tumour suppressor protein plays a key role in the integration of stress signals. Multi-site phosphorylation of p53 may play an integral part in the transmission of these signals and is catalysed by many different protein kinases including an unidentified p53-N-terminus-targeted protein kinase (p53NK) which phosphorylates a group of sites at the N-terminus of the protein. In this paper, we present evidence that the delta and epsilon isoforms of casein kinase 1 (CK1δ and CK1ε) show identical features to p53NK and can phosphorylate p53 both in vitro and in vivo. Recombinant, purified glutathione S-transferase (GST)-CK1δ and GST-CK1ε fusion proteins each phosphorylate p53 in vitro at serines 4, 6 and 9, the sites recognised by p53NK. Furthermore, p53NK (i) co-purifies with CK1δ/ε, (ii) shares identical kinetic properties to CK1δ/ε, and (iii) is inhibited by a CK1δ/ε-specific inhibitor (IC261). In addition, CK1δ is also present in purified preparations of p53NK as judged by immunoanalysis using a CK1δ-specific monoclonal antibody. Treatment of murine SV3T3 cells with IC261 specifically blocked phosphorylation in vivo of the CK1δ/ε phosphorylation sites in p53, indicating that p53 interacts physiologically with CK1δ and/or CK1ε. Similarly, over-expression of a green fluorescent protein (GFP)-CK1δ fusion protein led to hyper-phosphorylation of p53 at its N-terminus. Treatment of MethAp53ts cells with the topoisomerase-directed drugs etoposide or camptothecin led to increases in both CK1δ-mRNA and -protein levels in a manner dependent on the integrity of p53. These data suggest that p53 is phosphorylated by CK1δ and CK1ε and additionally that there may be a regulatory feedback loop involving p53 and CK1δ.

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Knippschild, U., Milne, D., Campbell, L. et al. p53 is phosphorylated in vitro and in vivo by the delta and epsilon isoforms of casein kinase 1 and enhances the level of casein kinase 1 delta in response to topoisomerase-directed drugs. Oncogene 15, 1727–1736 (1997). https://doi.org/10.1038/sj.onc.1201541

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  • DOI: https://doi.org/10.1038/sj.onc.1201541

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