Abstract
The tumour suppressor p53 protein integrates multiple signals regulating cell cycle progression and apoptosis. This regulation is mediated by several kinases that phosphorylate specific residues in the different functional domains of the p53 molecule. The human VRK1 protein is a new kinase related to a poxvirus kinase, and more distantly to the casein kinase 1 family. We have characterized the biochemical properties of human VRK1 from HeLa cells. VRK1 has a strong autophosphorylating activity in several Ser and Thr residues. VRK-1 phosphorylates acidic proteins, such as phosvitin and casein, and basic proteins such as histone 2b and myelin basic protein. Because some transcription factors are regulated by phosphorylation, we tested as substrates the N-transactivation domains of p53 and c-Jun fused to GST. Human c-Jun is not phosphorylated by VRK1. VRK1 phosphorylates murine p53 in threonine 18. This threonine is within the p53 hydrophobic loop (residues 13-23) required for the interaction of p53 with the cleft of its inhibitor mdm-2. The VRK1 C-terminus domain (residues 268-396) that contains a nuclear localization signal targets the protein to the nucleus, as determined by using fusion proteins with the green fluorescent protein. We conclude that VRK1 is an upstream regulator of p53 that belongs to a new signalling pathway.
Keywords
BiologyCasein kinase 1c-RafCasein kinase 2MAP2K7PhosphorylationKinaseMitogen-activated protein kinase kinaseProtein kinase AMAP kinase kinase kinaseCyclin-dependent kinase 2Molecular biologyCell biologyBiochemistry
MeSH Terms
3T3 CellsAmino Acid SequenceAnimalsBase SequenceBinding SitesCasein KinasesCatalytic DomainCell NucleusHeLa CellsHumansIntracellular Signaling Peptides and ProteinsMiceMolecular Sequence DataNuclear ProteinsPhosphorylationProtein KinasesProtein Serine-Threonine KinasesProteinsProto-Oncogene ProteinsProto-Oncogene Proteins c-mdm2Recombinant Fusion ProteinsSerineSubstrate SpecificityThreonineTranscription FactorsTumor Suppressor Protein p53Viral Proteins
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Publication Info
- Year
- 2000
- Type
- article
- Volume
- 19
- Issue
- 32
- Pages
- 3656-3664
- Citations
- 168
- Access
- Closed
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Cite This
Susana López-Borges,
Pedro A. Lazo
(2000).
The human vaccinia-related kinase 1 (VRK1) phosphorylates threonine-18 within the mdm-2 binding site of the p53 tumour suppressor protein.
Oncogene
, 19
(32)
, 3656-3664.
https://doi.org/10.1038/sj.onc.1203709
Identifiers
- DOI
- 10.1038/sj.onc.1203709
- PMID
- 10951572