Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:The human vaccinia-related kinase 1 (VRK1) phosphorylates threonine-18 within the mdm-2 binding site of the p53 tumour suppressor protein. 1095 72

The vaccinia-related kinase (VRK) proteins are a new group of three Ser-Thr kinases in the human kinome. VRK proteins are upstream regulators of several transcription factors. VRK1 phosphorylates p53 in Thr-18 within the region of binding to mdm2 preventing their interaction. The tissue distribution of three genes is still largely unknown. In the present report the expression of these genes was analyzed during murine hematopoietic development. The three genes are expressed in fetal liver and peripheral blood, with higher levels between days 11.5 and 13.5, a time when there is a massive expansion of liver cells, and thereafter their expression falls significantly. VRK genes are expressed, particularly at mid-gestation, in embryo thymus and spleen, but in adult thymus and spleen their levels are very low. VRK2 is expressed at lower levels than VRK1 and VRK3 in the mouse embryo. VRK genes play a role during embryonic development of hematopoiesis.
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PMID:Expression of the VRK (vaccinia-related kinase) gene family of p53 regulators in murine hematopoietic development. 1278 11

The VRK1 kinase is a novel Ser-Thr kinase in the human kinome that diverged from the casein kinase 1 branch. These kinases phosphorylate transcription factors related to stress responses, such as p53. In this report we have studied the phosphorylation of the transcription factor c-Jun in its N-terminal region. The VRK1 protein phosphorylates c-Jun with a Km of 0.4 muM, and is not inhibited by SP600125. VRK1 phosphorylates c-Jun in Ser63 and Ser73 in vitro, the same residues targeted by the N-terminal kinase of c-Jun (JNK). This phosphorylation induces the stabilization and accumulation of the c-Jun protein. VRK1 phosphorylates the endogenous c-Jun in Ser63. VRK1 activates c-Jun dependent transcription, which is dependent on phosphorylation of Ser63 and Ser73. The c-Jun with Ser63Ala and Ser73Ala substitutions is not transcriptionally active when cotransfected with VRK1. VRK1 interacts with c-Jun but not with JNK. The cotransfection of VRK1 and JNK has an additive effect on the transcriptional activation of c-Jun indicating that they can cooperate when both are at suboptimal dose; otherwise, maximum effect by one of them prevents the effect of the other. The VRK1-c-Jun connection represents a component of a new signaling pathway whose upstream elements remain to be identified.
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PMID:c-Jun phosphorylation by the human vaccinia-related kinase 1 (VRK1) and its cooperation with the N-terminal kinase of c-Jun (JNK). 1537 2

Variations in intracellular levels of p53 regulate many cellular functions and determine tumor susceptibility. Major mechanisms modulating p53 levels include phosphorylation and interaction of p53 with specific ubiquitin ligases that promote its degradation. N-terminal phosphorylation regulates the interaction of p53 with several regulatory molecules. Vaccinia-related kinase 1 (VRK1) is the prototype of a new Ser-Thr kinase family in the human kinome. VRK1 is located in the nucleus outside the nucleolus. Overexpression of VRK1 increases the stability of p53 by a posttranslational mechanism leading to its accumulation by a mechanism independent of the Chk2 kinase. Catalytically inactive VRK1 protein (a K179E mutant) does not induce p53 accumulation. VRK1 phosphorylates human p53 in Thr18 and disrupts p53-Mdm2 interaction in vitro, although a significant decrease in p53 ubiquitination by Mdm2 in vivo was not detected. VRK1 kinase does not phosphorylate Mdm2. VRK1-mediated p53 stabilization was also detected in Mdm2(-/-) cells. VRK1 also has an additive effect with MdmX or p300 to stabilize p53, and p300 coactivation and acetylation of p53 is enhanced by VRK1. The p53 stabilized by VRK1 is transcriptionally active. Suppression of VRK1 expression by specific small interfering RNA provokes several defects in proliferation, situating the protein in the regulation of this process. VRK1 might function as a switch controlling the proteins that interact with p53 and thus modifying its stability and activity. We propose VRK1 as the first step in a new pathway regulating p53 activity during cell proliferation.
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PMID:p53 Stabilization and accumulation induced by human vaccinia-related kinase 1. 1554 44

The vaccinia-related kinase (VRK) proteins are a new family with three members in the human kinome. The VRK1 protein phosphorylates several transcription factors and has been postulated to be involved in regulation of cell proliferation. In normal squamous epithelium, VRK1 is expressed in the proliferation area. Because VRK1 can stabilize p53, the expression of the VRK1 protein was analyzed in the context of the p53 pathway and the proliferation phenotype in a series of 73 head and neck squamous cell carcinomas. VRK1 protein level positively correlated with p53 response proteins, particularly hdm2 and p21. The VRK1 protein also correlated positively with several proteins associated with proliferation, such as cyclin-dependent kinase 2 (CDK2), CDK6, cdc2, cyclins B1 and A, topoisomerase II, survivin, and Ki67. The level of VRK1 protein behaves like a proliferation marker in this series of head and neck squamous cell carcinomas. To identify a possible regulatory role for VRK1 and because it regulates gene transcription, the promoters of two genes were studied, CDK2 and SURVIVIN, whose proteins correlated positively with VRK1. VRK1 increases the activity of both the CDK2 and SURVIVIN gene promoters. The expression of VRK1 was analyzed in the context of regulators of the G1-S transition. VRK1 protein levels increase in response to E2F1 and are reduced by retinoblastoma and p16. These data suggest that VRK1 might play a role in cell cycle regulation and is likely to represent the beginning of a new control mechanism of cell cycle, particularly late in the G1-S phase.
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PMID:VRK1 signaling pathway in the context of the proliferation phenotype in head and neck squamous cell carcinoma. 1654 55

VRK is a new kinase family of unknown function. Endogenous human vacinia-related kinase 2 (VRK2) protein is present in both the nucleus and the cytosol, which is a consequence of alternative splicing of two VRK2 messages coding for proteins of 508 and 397 amino acids, respectively. VRK2A has a C-terminal hydrophobic region that anchors the protein to membranes in the endoplasmic reticulum (ER) and mitochondria, and it colocalizes with calreticulin, calnexin and mitotracker; whereas VRK2B is detected in both the cytoplasm and the nucleus. VRK2A is expressed in all cell types, whereas VRK2B is expressed in cell lines in which VRK1 is cytoplasmic. Both VRK2 isoforms have an identical catalytic N-terminal domain and phosphorylate p53 in vitro uniquely in Thr18. Phosphorylation of the p53 protein in response to cellular stresses results in its stabilization by modulating its binding to other proteins. However, p53 phosphorylation also occurs in the absence of stress. Only overexpression of the nuclear VRK2B isoform induces p53 stabilization by post-translational modification, largely due to Thr18 phosphorylation. VRK2B may play a role in controlling the binding specificity of the N-terminal transactivation domain of p53. Indeed, the p53 phosphorylated by VRK2B shows a reduction in ubiquitination by Mdm2 and an increase in acetylation by p300. Endogenous p53 is also phosphorylated in Thr18 by VRK2B, promoting its stabilization and transcriptional activation in A549 cells. The relative phosphorylation of Thr18 by VRK2B is similar in magnitude to that induced by taxol, which might use a different signalling pathway. In this context, VRK2B kinase might functionally replace nuclear VRK1. Therefore, these kinases might be components of a new signalling pathway that is likely to play a role in normal cell proliferation.
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PMID:The subcellular localization of vaccinia-related kinase-2 (VRK2) isoforms determines their different effect on p53 stability in tumour cell lines. 1670 22

The stable accumulation of p53 is detrimental to the cell because it blocks cell growth and division. Therefore, increases in p53 levels are tightly regulated, mainly by its transcriptional target, mdm2, that downregulates p53. Elucidation of new signaling pathways requires the characterization of the members and the nature of their connection. Vaccinia-related kinase 1 (VRK1) contributes to p53 stabilization by partly interfering with its mdm2-mediated degradation, among other mechanisms; therefore, it is likely that some form of autoregulation between VRK1 and p53 must occur. We report here the identification of an autoregulatory loop between p53 and its stabilizing VRK1. There is an inverse correlation between VRK1 and p53 levels in cell lines, and induction of p53 by UV light downregulates VRK1 in fibroblasts. As the amount of p53 protein increases, there is a downregulation of the VRK1 protein level independent of its promoter. This effect is indirect but requires a transcriptionally active p53. The three most common transcriptionally inactive mutations detected in hereditary (Li-Fraumeni syndrome) and sporadic human cancer, p53(R175H), p53(R248W), and p53(R273H), as well as p53(R280K), are unable to induce downregulation of VRK1 protein. The p53 isoforms Delta40p53 and p53beta, lacking the transactivation and oligomerization domains, respectively, do not downregulate VRK1. VRK1 downregulation induced by p53 is independent of mdm2 activity and proteasome-mediated degradation since it occurs in the presence of proteasome inhibitors and in mdm2-deficient cells. The degradation of VRK1 is sensitive to chloroquine, an inhibitor of the late endosome-lysosome transport, and to serine protease inhibitors of the lysosomal pathway.
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PMID:p53 downregulates its activating vaccinia-related kinase 1, forming a new autoregulatory loop. 1678 68

The human VRK1 is a new ser-thr kinase expressed in many cell types. VRK1 is a regulator of p53 and other transcription factors related with cellular responses to stress. The human VRK1 protein has a dominant epitope located in its C-terminal region, between residues 333 and 396, which is detected by different antibodies. All the antibodies detect the same protein in immunoblots and immunoprecipitations. But the antibodies have a different reactivity when a single aminoacid substitution in T355, mimicking phosphorylation, is introduced next to the nuclear localization signal. These differences in reactivity permit the identification of different intracellular subpopulations. Most of the intracellular VRK1 protein is nuclear, but in some cells it is also detected in the cytosol, depending on the type of tissue. These different locations are detected by immunohistochemistry of human biopsies and immunofluorescence of cell lines. Some antibodies identify a subpopulation within the vesicular system, particularly in the Golgi apparatus. The different reactivity of the VRK1 protein indicates that this protein has a subcellular localization that can be regulated, thus adding an additional level of regulatory complexity to the VRK1 protein.
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PMID:Identification of a dominant epitope in human vaccinia-related kinase 1 (VRK1) and detection of different intracellular subpopulations. 1761 71

Human VRK1 (vaccinia-related kinase 1) is a novel serine-threonine kinase that regulates several transcription factors, including p53, ATF2 and c-Jun; and its loss results in defects of cell proliferation. VRK1 stabilizes p53 and the accumulated p53 downregulates VRK1 forming an autoregulatory loop. Wild-type p53, but not mutant p53, was able to downregulate VRK1 in the A549 lung carcinoma cell line. VRK1 expression has been studied in human lung carcinomas. VRK1 protein level was significantly higher in squamous cell lung carcinomas than in adenocarcinomas, and inversely correlated with p16. Tumours with p53 mutations have a positive trend with those having very high levels of VRK1 protein, particularly in squamous cell lung carcinomas. These data indicate that the VRK1-p53 autoregulatory loop was not functional in a group of lung carcinomas. The accumulation of VRK1 in tumours with mutant p53 could result in stimulation of other signalling pathways that can contribute to tumour growth and progression in addition to those resulting from loss of p53 function.
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PMID:Alteration of the VRK1-p53 autoregulatory loop in human lung carcinomas. 1768 19

The kinase VRK1 has been implicated in mitotic and meiotic progression in invertebrate species, but whether it mediates these events during mammalian gametogenesis is not completely understood. Previous work has demonstrated a role for mammalian VRK1 in proliferation of male spermatogonia, yet whether VRK1 plays a role in meiotic progression, as seen in Drosophila, has not been determined. Here, we have established a mouse strain bearing a gene trap insertion in the VRK1 locus that disrupts Vrk1 expression. In addition to the male proliferation defects, we find that reduction of VRK1 activity causes a delay in meiotic progression during oogenesis, results in the presence of lagging chromosomes during formation of the metaphase plate, and ultimately leads to the failure of oocytes to be fertilized. The activity of at least one phosphorylation substrate of VRK1, p53, is not required for these defects. These results are consistent with previously defined functions of VRK1 in meiotic progression in Drosophila oogenesis, and indicate a conserved role for VRK1 in coordinating proper chromosomal configuration in female meiosis.
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PMID:The kinase VRK1 is required for normal meiotic progression in mammalian oogenesis. 2127 75


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