Protein kinase CK1delta phosphorylates key sites in the acidic domain of murine double-minute clone 2 protein (MDM2) that regulate p53 turnover
| Autor: | R. Kulikov, Christine Blattner, D M Milne, David W. Meek, Uwe Knippschild, Sylvia Dias, Markus Winter |
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| Rok vydání: | 2004 |
| Předmět: |
Molecular Sequence Data
Mitogen-activated protein kinase kinase Biochemistry Proto-Oncogene Proteins Chlorocebus aethiops Serine Animals Humans Protein phosphorylation c-Raf Amino Acid Sequence Phosphorylation Protein kinase A Protein kinase B Serine/threonine-specific protein kinase biology Nuclear Proteins Proto-Oncogene Proteins c-mdm2 Ubiquitin ligase Protein Structure Tertiary enzymes and coenzymes (carbohydrates) Casein Kinase Idelta COS Cells biology.protein Tumor Suppressor Protein p53 cGMP-dependent protein kinase HeLa Cells |
| Zdroj: | Biochemistry. 43(51) |
| ISSN: | 0006-2960 |
| Popis: | Murine double-minute clone 2 protein (MDM2) is an E3 ubiquitin ligase that regulates the turnover of several cellular factors including the p53 tumor suppressor protein. As part of the mechanism of p53 induction in response to DNA damage, a cluster of serine residues within the central acidic domain of MDM2 become hypophosphorylated, leading to attenuation of MDM2-mediated p53 destruction. In the present study, we identify the protein kinase CK1delta as a major cellular activity that phosphorylates MDM2. Amino acid substitution, coupled with phosphopeptide analyses, indicates that several serine residues in the acidic domain, including Ser-240, Ser-242, and Ser-246, as well as Ser-383 in the C-terminal region, are phosphorylated by CK1delta in vitro. We also show, through expression of a dominant negative mutant of CK1delta or treatment of cells with IC261, a CK1delta-selective inhibitor, that MDM2 is phosphorylated by CK1delta in cultured cells. These data establish the identity of a key signaling molecule that promotes the phosphorylation of a major regulatory region in MDM2 under normal growth conditions. |
| Databáze: | OpenAIRE |
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