Oncogenic Sox2 regulates and cooperates with VRK1 in cell cycle progression and differentiation

Moura, David S.; Fernández, Isabel F.; Marín-Royo, Gema; López-Sánchez, Inmaculada; Martín-Doncel, Elena; Vega, Francisco; Lazo, Pedro A.

doi:10.1038/srep28532

Cited by 20 publications

(44 citation statements)

References 68 publications

(166 reference statements)

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“…VRK1 role in the regulation of chromatin organization and associated functions can vary depending on local protein interactions and the stage of the cell cycle. VRK1 as a chromatin kinase plays a role in the regulation of transcription factors [ 42 – 44 ], and in chromatin reorganization in DNA-damage responses [ 26 , 33 , 45 – 47 ]. Therefore, the formation of a stable protein complex, formed by VRK1 and AURKB, is a likely player in different temporal and functional aspects of chromatin remodelling during mitosis.…”

Section: Discussionmentioning

confidence: 99%

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VRK1 and AURKB form a complex that cross inhibit their kinase activity and the phosphorylation of histone H3 in the progression of mitosis

Moura

Campillo-Marcos

Vázquez-Cedeira

et al. 2018

Cell. Mol. Life Sci.

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Regulation of cell division requires the integration of signals implicated in chromatin reorganization and coordination of its sequential changes in mitosis. Vaccinia-related kinase 1 (VRK1) and Aurora B (AURKB) are two nuclear kinases involved in different steps of cell division. We have studied whether there is any functional connection between these two nuclear kinases, which phosphorylate histone H3 in Thr3 and Ser10, respectively. VRK1 and AURKB are able to form a stable protein complex, which represents only a minor subpopulation of each kinase within the cell and is detected following nocodazole release. Each kinase is able to inhibit the kinase activity of the other kinase, as well as inhibit their specific phosphorylation of histone H3. In locations where the two kinases interact, there is a different pattern of histone modifications, indicating that there is a local difference in chromatin during mitosis because of the local complexes formed by these kinases and their asymmetric intracellular distribution. Depletion of VRK1 downregulates the gene expression of BIRC5 (survivin) that recognizes H3-T3ph, both are dependent on the activity of VRK1, and is recovered with kinase active murine VRK1, but not with a kinase-dead protein. The H3–Thr3ph–survivin complex is required for AURB recruitment, and their loss prevents the localization of ACA and AURKB in centromeres. The cross inhibition of the kinases at the end of mitosis might facilitate the formation of daughter cells. A sequential role for VRK1, AURKB, and haspin in the progression of mitosis is proposed.Electronic supplementary materialThe online version of this article (10.1007/s00018-018-2746-7) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

“…Proteins were transferred to PVDF Immobilon - P or Immobilon - FL membranes (Millipore) as previously reported [28, 36, 47, 67]. PDVF membranes were incubated with the specific primary antibody (Table 1).…”

Section: Methodsmentioning

confidence: 99%

VRK1 and AURKB form a complex that cross inhibit their kinase activity and the phosphorylation of histone H3 in the progression of mitosis

Moura

Campillo-Marcos

Vázquez-Cedeira

et al. 2018

Cell. Mol. Life Sci.

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“…An additional role of VRK1 as a chromatin kinase is its association with transcriptional complexes, where it interacts and phosphorylates several transcription factors that include p53 [ 28 ], CREB [ 35 ], ATF2 [ 36 ], c-Jun [ 37 ], Sox2 [ 38 ], and the farnesoid X receptor (FXR) [ 39 ].…”

Section: Vrk1 Roles In Chromatinmentioning

confidence: 99%

Implication of the VRK1 chromatin kinase in the signaling responses to DNA damage: a therapeutic target?

Campillo-Marcos

Lazo

2018

Cell. Mol. Life Sci.

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DNA damage causes a local distortion of chromatin that triggers the sequential processes that participate in specific DNA repair mechanisms. This initiation of the repair response requires the involvement of a protein whose activity can be regulated by histones. Kinases are candidates to regulate and coordinate the connection between a locally altered chromatin and the response initiating signals that lead to identification of the type of lesion and the sequential steps required in specific DNA damage responses (DDR). This initiating kinase must be located in chromatin, and be activated independently of the type of DNA damage. We review the contribution of the Ser-Thr vaccinia-related kinase 1 (VRK1) chromatin kinase as a new player in the signaling of DNA damage responses, at chromatin and cellular levels, and its potential as a new therapeutic target in oncology. VRK1 is involved in the regulation of histone modifications, such as histone phosphorylation and acetylation, and in the formation of γH2AX, NBS1 and 53BP1 foci induced in DDR. Induction of DNA damage by chemotherapy or radiation is a mainstay of cancer treatment. Therefore, novel treatments can be targeted to proteins implicated in the regulation of DDR, rather than by directly causing DNA damage.

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“…Kinase assays were performed as previously described 31,34,35 . Briefly, in vitro kinase assays with [ 32 ‐ P]‐γATP were performed with GST‐VRK1 wild‐type, or the p.Y213H variant 7,31,36 . Kinase assays with the following substrates were previously published: histone H3, 13,33 H2AX, 13 p53, 37,38 53BP1, 39 and coilin 7 .…”

Section: Patient Materials and Methodsmentioning

confidence: 99%

VRK1 (Y213H) homozygous mutant impairs Cajal bodies in a hereditary case of distal motor neuropathy

Marcos¹,

Martín-Doncel

Morejón‐García

et al. 2020

Ann Clin Transl Neurol

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Background Distal motor neuropathies with a genetic origin have a heterogeneous clinical presentation with overlapping features affecting distal nerves and including spinal muscular atrophies and amyotrophic lateral sclerosis. This indicates that their genetic background is heterogeneous. Patient and methods In this work, we have identified and characterized the genetic and molecular base of a patient with a distal sensorimotor neuropathy of unknown origin. For this study, we performed whole‐exome sequencing, molecular modelling, cloning and expression of mutant gene, and biochemical and cell biology analysis of the mutant protein. Results A novel homozygous recessive mutation in the human VRK1 gene, coding for a chromatin kinase, causing a substitution (c.637T > C; p.Tyr213His) in exon 8, was detected in a patient presenting since childhood a progressive distal sensorimotor neuropathy and spinal muscular atrophy syndrome, with normal intellectual development. Molecular modelling predicted this mutant VRK1 has altered the kinase activation loop by disrupting its interaction with the C‐terminal regulatory region. The p.Y213H mutant protein has a reduced kinase activity with different substrates, including histones H3 and H2AX, proteins involved in DNA damage responses, such as p53 and 53BP1, and coilin, the scaffold for Cajal bodies. The mutant VRK1(Y213H) protein is unable to rescue the formation of Cajal bodies assembled on coilin, in the absence of wild‐type VRK1. Conclusion The VRK1(Y213H) mutant protein alters the activation loop, impairs the kinase activity of VRK1 causing a functional insufficiency that impairs the formation of Cajal bodies assembled on coilin, a protein that regulates SMN1 and Cajal body formation.

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Oncogenic Sox2 regulates and cooperates with VRK1 in cell cycle progression and differentiation

Cited by 20 publications

References 68 publications

VRK1 and AURKB form a complex that cross inhibit their kinase activity and the phosphorylation of histone H3 in the progression of mitosis

VRK1 and AURKB form a complex that cross inhibit their kinase activity and the phosphorylation of histone H3 in the progression of mitosis

Implication of the VRK1 chromatin kinase in the signaling responses to DNA damage: a therapeutic target?

VRK1 (Y213H) homozygous mutant impairs Cajal bodies in a hereditary case of distal motor neuropathy

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