Atlas of Genetics and Cytogenetics in Oncology and Haematology
VRK1 (Vaccinia-related kinase 1)
| Identity |
| Other names | VRK-1 |
| MGC117401 | |
| MGC138280 | |
| MGC142070 | |
| vaccinia related kinase 1 | |
| Serine/threonine-protein kinase VRK1 | |
| Vaccinia-related kinase 1 | |
| HGNC | VRK1 |
| Location | 14q32.2 |
| Local_order | Centromere-----PAPOLA--VRK1--BCL11B------Telomere. |
| DNA/RNA |
 | |
| 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. | |
| Description | 13 exons in 84.22 kilobases. Transcription initiated from cetromere to telomere direction. |
| Transcription | Initiation codon located in exon 2. Normal message is 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. |
| 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). |
| Protein |
 | |
| ABRS: ATP-binding region signature SRPKAS: Ser/Thr protein kinases active-site signature ELTS:Endosomal-lysosomal targeting sequence NLS: Nuclear localization signal | |
| Note | Enzyme Number (IUBMB): "EC 2.7.11.1". |
| Description | 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. |
| 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. |
| Localisation | 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. |
| 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-dependent-transcription 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 C-terminal 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 different protein interactions and thus of differential regulation. |
| Mutations |
| Note | All mutations reported in study by Greenman el al. 2007. |
| 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). |
| Somatic | Colorectal carcinoma: Heterozygous mutation in nucleotide 42 in the cDNA coding region; T to C (silent S14S). |
| Implicated in |
| Entity | 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). |
| Entity | Head and neck squamous cell carcinoma. |
| Oncogenesis | Overexpression of VRK1 protein that positively correlates with hdm2, cdk2, cdk4 and survivin. |
| Entity | Neuroblastomas |
| Cytogenetics | Loss of heterozygosis (31 %) in marker (D14S987) in 14q32.2 which is located 5' with respect to the VRK1 gene. |
| Entity | 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. |
| Entity | Nasopharyngeal carcinoma |
| Cytogenetics | Loss of heterozygosis in marker (D14S51) in 14q32.2 which is located 0.15Mb 3' to the VRK1 gene. |
| Entity | Chronic myelogenous leukemia (Blastic crisis) |
| Cytogenetics | Loss of heterozygosis in marker (D14S65) in 14q32.2 which is located 0.15Mb 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. | |
| External links |
| Bibliography |
| Identification of two novel human putative serine/threonine kinases, VRK1 and VRK2, with structural similarity to vaccinia virus B1R kinase. |
| Nezu J, Oku A, Jones MH, Shimane M |
| Genomics. 1997 ; 45 (2) : 327-331. |
| PMID 9344656 |
| Loss of heterozygosity on chromosome 14 in nasopharyngeal carcinoma. |
| Mutirangura A, Pornthanakasem W, Sriuranpong V, Supiyaphun P, Voravud N |
| International journal of cancer. Journal international du cancer. 1998 ; 78 (2) : 153-156. |
| PMID 9754644 |
| Loss of heterozygosity of 14q32 in colorectal carcinoma. |
| Bando T, Kato Y, Ihara Y, Yamagishi F, Tsukada K, Isobe M |
| Cancer genetics and cytogenetics. 1999 ; 111 (2) : 161-165. |
| PMID 10347556 |
| Isolation and mapping of a polymorphic CA repeat sequence at the human VRK1 locus. |
| Sugimoto J, Yamauchi T, Hatakeyama T, Isobe M |
| Journal of human genetics. 1999 ; 44 (2) : 133-134. |
| PMID 10083742 |
| Detailed deletion mapping of chromosome band 14q32 in human neuroblastoma defines a 1.1-Mb region of common allelic loss. |
| Hoshi M, Otagiri N, Shiwaku HO, Asakawa S, Shimizu N, Kaneko Y, Ohi R, Hayashi Y, Horii A |
| British journal of cancer. 2000 ; 82 (11) : 1801-1807. |
| PMID 10839294 |
| The human vaccinia-related kinase 1 (VRK1) phosphorylates threonine-18 within the mdm-2 binding site of the p53 tumour suppressor protein. |
| Lopez-Borges S, Lazo PA |
| Oncogene. 2000 ; 19 (32) : 3656-3664. |
| PMID 10951572 |
| Consistent loss of heterozygosity at 14Q32 in lymphoid blast crisis of chronic myeloid leukemia. |
| Sercan HO, Sercan ZY, Kizildag S, Undar B, Soydan S, Sakizli M |
| Leukemia & lymphoma. 2000 ; 39 (3-4) : 385-390. |
| PMID 11342319 |
| Kinetic properties of p53 phosphorylation by the human vaccinia-related kinase 1. |
| Barcia R, Lˆ„pez-Borges S, Vega FM, Lazo PA |
| Archives of biochemistry and biophysics. 2002 ; 399 (1) : 1-5. |
| PMID 11883897 |
| Activation of HOX11L2 by juxtaposition with 3'-BCL11B in an acute lymphoblastic leukemia cell line (HPB-ALL) with t(5;14)(q35;q32.2). |
| MacLeod RA, Nagel S, Kaufmann M, Janssen JW, Drexler HG |
| Genes, chromosomes & cancer. 2003 ; 37 (1) : 84-91. |
| PMID 12661009 |
| The cardiac homeobox gene NKX2-5 is deregulated by juxtaposition with BCL11B in pediatric T-ALL cell lines via a novel t(5;14)(q35.1;q32.2). |
| Nagel S, Kaufmann M, Drexler HG, MacLeod RA |
| Cancer research. 2003 ; 63 (17) : 5329-5334. |
| PMID 14500364 |
| Expression of the VRK (vaccinia-related kinase) gene family of p53 regulators in murine hematopoietic development. |
| Vega FM, Gonzalo P, Gaspar ML, Lazo PA |
| FEBS letters. 2003 ; 544 (1-3) : 176-180. |
| PMID 12782311 |
| Identification of target genes of the p16INK4A-pRB-E2F pathway. |
| Vernell R, Helin K, Mˆºller H |
| The Journal of biological chemistry. 2003 ; 278 (46) : 46124-46137. |
| PMID 12923195 |
| Members of a novel family of mammalian protein kinases complement the DNA-negative phenotype of a vaccinia virus ts mutant defective in the B1 kinase. |
| Boyle KA, Traktman P |
| Journal of virology. 2004 ; 78 (4) : 1992-2005. |
| PMID 14747564 |
| Characterization of three paralogous members of the Mammalian vaccinia related kinase family. |
| Nichols RJ, Traktman P |
| The Journal of biological chemistry. 2004 ; 279 (9) : 7934-7946. |
| PMID 14645249 |
| c-Jun phosphorylation by the human vaccinia-related kinase 1 (VRK1) and its cooperation with the N-terminal kinase of c-Jun (JNK). |
| Sevilla A, Santos CR, Barcia R, Vega FM, Lazo PA |
| Oncogene. 2004 ; 23 (55) : 8950-8958. |
| PMID 15378002 |
| Characterization of three paralogous members of the Mammalian vaccinia related kinase family. |
| Nichols RJ, Traktman P |
| The Journal of biological chemistry. 2004 ; 279 (9) : 7934-7946. |
| PMID 14645249 |
| p53 Stabilization and accumulation induced by human vaccinia-related kinase 1. |
| Vega FM, Sevilla A, Lazo PA |
| Molecular and cellular biology. 2004 ; 24 (23) : 10366-10380. |
| PMID 15542844 |
| Vaccinia-related kinase-1. |
| Lazo PA, Vega FM, Sevilla A |
| Afcs Nature Molecule Page. 2005. |
| The vaccinia-related kinases phosphorylate the N' terminus of BAF, regulating its interaction with DNA and its retention in the nucleus. |
| Nichols RJ, Wiebe MS, Traktman P |
| Molecular biology of the cell. 2006 ; 17 (5) : 2451-2464. |
| PMID 16495336 |
| VRK1 signaling pathway in the context of the proliferation phenotype in head and neck squamous cell carcinoma. |
| Santos CR, Rodrˆ‚guez-Pinilla M, Vega FM, Rodrˆ‚guez-Peralto JL, Blanco S, Sevilla A, Valbuena A, Hernˆ°ndez T, van Wijnen AJ, Li F, de Alava E, Sˆ°nchez-Cˆ©spedes M, Lazo PA |
| Molecular cancer research : MCR. 2006 ; 4 (3) : 177-185. |
| PMID 16547155 |
| p53 downregulates its activating vaccinia-related kinase 1, forming a new autoregulatory loop. |
| Valbuena A, Vega FM, Blanco S, Lazo PA |
| Molecular and cellular biology. 2006 ; 26 (13) : 4782-4793. |
| PMID 16782868 |
| Patterns of somatic mutation in human cancer genomes. |
| 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 G, Buck G, Choudhury B, Clements J, Cole J, Dicks E, Forbes S, Gray K, Halliday K, Harrison R, Hills K, Hinton J, Jenkinson A, Jones D, Menzies A, Mironenko T, Perry J, Raine K, Richardson D, Shepherd R, Small A, Tofts C, Varian J, Webb T, West S, Widaa S, Yates A, Cahill DP, Louis DN, Goldstraw P, Nicholson AG, Brasseur F, Looijenga L, Weber BL, Chiew YE, DeFazio A, Greaves MF, Green AR, Campbell P, Birney E, Easton DF, Chenevix-Trench G, Tan MH, Khoo SK, Teh BT, Yuen ST, Leung SY, Wooster R, Futreal PA, Stratton MR |
| Nature. 2007 ; 446 (7132) : 153-158. |
| PMID 17344846 |
| Activation of TLX3 and NKX2-5 in t(5;14)(q35;q32) T-cell acute lymphoblastic leukemia by remote 3'-BCL11B enhancers and coregulation by PU.1 and HMGA1. |
| Nagel S, Scherr M, Kel A, Hornischer K, Crawford GE, Kaufmann M, Meyer C, Drexler HG, MacLeod RA |
| Cancer research. 2007 ; 67 (4) : 1461-1471. |
| PMID 17308084 |
| REVIEW articles | automatic search in PubMed |
| Last year publications | automatic search in PubMed |
| Contributor(s) |
| Written | 04-2007 | 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, Salamanca, Spain. |
| Citation |
| This paper should be referenced as such : |
| Lazo PA, Vega FM, Sevilla A, Valbuena A, Sanz-Garcia M, Lopez-Sanchez I, Blanco S . VRK1 (Vaccinia-related kinase 1). Atlas Genet Cytogenet Oncol Haematol. April 2007 . URL : http://AtlasGeneticsOncology.org/Genes/VRK1ID43556ch14q32.html |
| © Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Mon Aug 11 21:18:25 2008 |
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