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Closed Access item The human vaccinia-related kinase 1 (VRK1) phosphorylates threonine-18 within the mdm-2 binding site of the p53 tumour suppressor protein
Lazo, Pedro A.
|Keywords:||VRK1, p53, mdm2, kinase|
|Citation:||Oncogene 19(32): 3656-3664 (2000)|
|Abstract:||The tumour suppressor p53 protein integrates multiple
signals regulating cell cycle progression and apoptosis.
This regulation is mediated by several kinases that
phosphorylate speci®c residues in the di erent 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 autopho-
sphorylating 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 ¯uorescent
protein. We conclude that VRK1 is an upstream
regulator of p53 that belongs to a new signalling
pathway. Oncogene (2000) 19, 3656 ± 3664.|
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