Download Gene Section VRK1 (Vaccinia-related kinase 1) Atlas of Genetics and Cytogenetics

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VRK1 (Vaccinia-related kinase 1)
Pedro A Lazo, Francisco M Vega, Ana Sevilla, Alberto Valbuena, Marta Sanz-Garcia,
Inmaculada Lopez-Sanchez, Sandra Blanco
Instituto de Biologia Molecular y Celular del Cancer, CSIC-Universidad de Salamanca, campus Miguel de
Unamuno, E-37007 Salamanca, Spain
Published in Atlas Database: April 2007
Online updated version: http://AtlasGeneticsOncology.org/Genes/VRK1ID43556ch14q32.html
DOI: 10.4267/2042/15901
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 2007 Atlas of Genetics and Cytogenetics in Oncology and Haematology
1702 nucleotides. Some alternatively spliced RNA
messages have been detected; but they are likely to
represent splicing intermediates since there is no
protein has been detected expressed from these
alternative messages in humans.
Identity
Hugo: VRK1
Other names: VRK-1; MGC117401; MGC138280;
MGC142070;
Vaccinia related kinase 1;
Serine/threonine-protein kinase VRK1;
Vaccinia-related kinase 1
Location: 14q32.2
Local
order:
Centromere---PAPOLA--VRK1-BCL11B---Telomere.
Pseudogene
None.
There are two closely related genes VRK2 and VRK3.
SNP: 289 single nucleotide polymorphisms identified
in human VRK1.
ALLELE VARIANTS: CA Polymorphisms. Near the
PAPOLA (Polyadenyl polymerase) with respect to
VRK1 there is a polymorphic dinucleotide (CA)
sequence that has high heterozygosity (0.81). Might be
a useful marker in the genetic study of disorders
localized at the 14q32 region, such as autosomal
recessive congenital microphthalmia (CMIC).
DNA/RNA
Description
13 exons in 84.22 kilobases. Transcription initiated
from cetromere to telomere direction.
Transcription
Initiation codon located in exon 2. Normal message is
VRK1 gene structure based on data available in the Ensembl release 43. Upstream non-coding exons (green). Coding exons (yellow), 3'
unstranslated sequence (red). The size of the exons in nucleotides is indicated below each exon. Exon number is indicated within the
exon.
Atlas Genet Cytogenet Oncol Haematol. 2007;11(4)
285
VRK1 (Vaccinia-related kinase 1)
Lazo PA et al.
ABRS: ATP-binding region signature
SRPKAS: Ser/Thr protein kinases active-site signature
ELTS: Endosomal-lysosomal targeting sequence
NLS: Nuclear localization signal
different protein interactions and thus of differential
regulation.
Protein
Note: Enzyme Number (IUBMB): 'EC 2.7.11.1'.
Mutations
Description
Note: All mutations reported in study by Greenman el
al., 2007.
Protein of 396 aminoacids. 46 kDa. Serine-threonine
kinase domain (residues 26-300). Nuclear localization
signal
(in
C-terminal
region).
Protein
autophosphorylated in several residues.
Germinal
Normal:
Mutation in nucleotide 45 in the cDNA coding region;
A to G that is silent (A15A).
Mutation in nucleotide 705 in the cDNA coding region;
C to T that is silent (G235G).
Expression
VRK1 is widely expressed in proliferating cells, normal
and tumoral. It is not present in quiescent or
differentiated cells that do not divide in human
biopsies.
Somatic
Localisation
Colorectal carcinoma: Heterozygous mutation in
nucleotide 42 in the cDNA coding region; T to C (silent
S14S).
Subcellular localisation varies depending on cell type
and growth conditions. Most commonly VRK1 is
expressed and detected in the nucleus, excluding the
nucleolus. However, in some cells it is in the cytosol,
particularly associated with endoplasmic reticulum and
Golgi.
Occasionally it is observed in the nucleolus, but outside
the nucleus. The regulation of the subcellular
localization is unknown.
Implicated in
T-cell acute lymphoblastic leukemia
Cytogenetics
Translocation t(5;14)(q35;q32). BCR (Breakpoint
cluster region), detected as a DNAseI hypersensitive
site between VRK1 and BCL11B in T-cell acute
lymphoblastic leukemia with t(5,14)(q35;q32).
Hybrid/Mutated Gene
Disregulation of TLX3 and NKX2-5 homeobox genes,
but not of VRK1.
Abnormal Protein
None.
Oncogenesis
In this translocation the breakpoint occurs in a DNAseI
hypersensitive site located between VRK1 and
BCL11B genes; but the structure, or expression, of
VRK1 does not appear to be affected. In this
translocation there is a dysregulation of TLX3 and
NKX2-5 homeobox genes (both on chromosome 5).
Function
Serine-threonine kinase activity.
Phosphorylates p53 in Threonine-18 preventing its
interaction with Hdm2 and activates p53-dependent
transcription. Phosphorylates c-Jun and ATF2
transcription factors. VRK1 also phosphorylates BAF1
required for nuclear envelope assembly.
In human cell lines siRNA specific for VRK1 results in
defective cell proliferation. The level of VRK1 protein
is regulated proteolytically by a p53-dependenttranscription mechanism. This mechanism results in the
induction of a targeting of VRK1 to enter the
endosomal-lysosomal pathway.
Homology
The kinase domain is highly homologous to that in
other ser-thr kinases. The C-terminal region has no
homology to any known protein or domain. This Cterminal region of VRK1 is different form that in
human VRK2, or in the VRK-1 homolog of distant
species such as Drosophila, C. elegans or Dario Rerio.
This C-terminal divergence suggest the possibility of
Atlas Genet Cytogenet Oncol Haematol. 2007;11(4)
Head and neck squamous cell
carcinoma
Oncogenesis
Overexpression of VRK1 protein that positively
correlates with hdm2, cdk2, cdk4 and survivin.
286
VRK1 (Vaccinia-related kinase 1)
Lazo PA et al.
Neuroblastomas
Nasopharyngeal carcinoma
Cytogenetics
Loss of heterozygosis (31 %) in marker (D14S987) in
14q32.2 which is located 5' with respect to the VRK1
gene.
Cytogenetics
Loss of heterozygosis in marker (D14S51) in 14q32.2
which is located 0.15 Mb 3' to the VRK1 gene.
Chronic myelogenous leukemia (Blastic
crisis)
Colorectal carcinoma
Cytogenetics
Loss of heterozygosis (40-60 %) depending on markers
(D14S65; D14S250; D14S5267) in 14q32.2 which is
located 3' to the VRK1 gene at less than 0.3 Mb.
D14S65 is 0.15 Mb 3' with respect to VRK1.
Cytogenetics
Loss of heterozygosis in marker (D14S65) in 14q32.2
which is located 0.15 Mb 3' to the VRK1 gene.
Breakpoints
Localization of loss of heterozygosis (LOH) and translocation breakpoints reported in 14q32.2. The breakpoint cluster region has
multiple DNAseI hypersensitive sites.
MacLeod RA, Nagel S, Kaufmann M, Janssen JW, Drexler HG.
Activation of HOX11L2 by juxtaposition with 3'-BCL11B in an
acute lymphoblastic leukemia cell line (HPB-ALL) with
t(5;14)(q35;q32.2). Genes Chromosomes Cancer 2003;37:8491.
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This article should be referenced as such:
Lazo PA, Vega FM, Sevilla A, Valbuena A, Sanz-García M,
López-Sanchez I, Blanco S. VRK1 (Vaccinia-related kinase 1).
Atlas Genet Cytogenet Oncol Haematol.2007;11(4):285-288.
Greenman C, Stephens P, Smith R, Dalgliesh GL, Hunter C,
Bignell G, Davies H, Teague J, Butler A, Stevens C, Edkins S,
O'Meara S, Vastrik I, Schmidt EE, Avis T, Barthorpe S, Bhamra
Atlas Genet Cytogenet Oncol Haematol. 2007;11(4)
288