| Autor: |
Knippschild, U, Milne, D M, Campbell, L E, DeMaggio, A J, Christenson, E, Hoekstra, M F, Meek, D W |
| Předmět: |
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| Zdroj: |
Oncogene; 10/2/97, Vol. 15 Issue 14, p1727, 10p |
| Abstrakt: |
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. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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