The vaccinia virus B1R kinase induces p53 downregulation by an Mdm2-dependent mechanism

Santos, Cláudio R.; Vega, Francisco; Blanco, Sandra; Barcia, Ramiro; Lazo, Pedro A.

doi:10.1016/j.virol.2004.08.013

Cited by 44 publications

(61 citation statements)

References 50 publications

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“…4B), were phosphorylated, suggesting that the phosphorylation was very complex since it occurred in multiple sites throughout the JIP1 molecule. This situation was already observed with p53, which is also hyperphosphorylated by B1R (37). The autophosphorylation of B1R was also detected in the assay.…”

Section: Accumulation Of C-jun During Vaccinia Virus Infectionsupporting

confidence: 68%

“…The accumulation of c-Jun may also be due to phosphorylation as a consequence of an infection by an early viral kinase. The only early vaccinia kinase (B1R) has been shown to hyperphosphorylate and destabilize p53, another stress response protein (37). Therefore, whether B1R could have an effect on c-Jun stability was determined.…”

Section: Accumulation Of C-jun During Vaccinia Virus Infectionmentioning

confidence: 99%

“…Also, it was impossible to generate a virus lacking the B1R open reading frame, which shows that it is an essential gene even without kinase activity (2), probably because of its ability to modulate other proteins by a direct interaction. So far, the identification of B1R substrates, either viral or cellular, is very limited; among its viral protein substrates is H5R (3), and among the cellular substrates are ribosomal proteins (1,4), BAF (30), and p53, which is hyperphosphorylated, triggering a downregulation of apoptotic signals (37) that could contribute to the survival of infected cells by transiently interfering with the cellular stress response and thus allowing the course of the infection to progress.…”

mentioning

confidence: 99%

“…apoptosis (54) and vaccinia-infected cells show a decrease in p53 protein levels (48), which is probably induced by B1R (37). A functional consequence of the expression of B1R in the cell and its interaction with the JNK and p53 response pathways (37) is that B1R might make the cell less sensitive to cell death.…”

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confidence: 99%

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Vaccinia Virus B1R Kinase Interacts with JIP1 and Modulates c-Jun-Dependent Signaling

Santos

Blanco

Sevilla

et al. 2006

J Virol

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Viruses have to adjust to the host cell to guarantee their life cycle and survival. This aspect of the virus-host cell interaction is probably performed by viral proteins, such as serine-threonine kinases, that are present early during infection. Vaccinia virus has an early Ser-Thr kinase, B1R, which, although required for successful viral infection, is poorly characterized regarding its effects on cellular proteins, and thus, its potential contribution to pathogenesis is not known. Signaling by mitogen-activated protein kinase (MAPK) is mediated by the assembly of complexes between these kinases and the JIP scaffold proteins. To understand how vaccinia virus B1R can affect the host, its roles in the cellular signaling by MAPK complexes and c-Jun activation have been studied. Independently of its kinase activity, B1R can interact with the central region of the JIP1 scaffold protein. The B1R-JIP1 complex increases the amount of MAPK bound to JIP1; thus, MKK7 and TAK1 either bind with higher affinity or bind more stably to JIP1, while there is an increase in the phosphorylation state of JNK bound to JIP1. The functional consequence of these more stable interactions is an increase in the activity of transcription factors, such as c-Jun, that respond to these complexes. Furthermore, B1R is also able to directly phosphorylate c-Jun in residues different from those targeted by JNK and, thus, B1R can also cooperate by an independent route in c-Jun activation. Vaccinia virus B1R can thus modulate the signaling of pathways that respond to cellular stress.

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Section: Accumulation Of C-jun During Vaccinia Virus Infectionsupporting

confidence: 68%

Section: Accumulation Of C-jun During Vaccinia Virus Infectionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Vaccinia Virus B1R Kinase Interacts with JIP1 and Modulates c-Jun-Dependent Signaling

Santos

Blanco

Sevilla

et al. 2006

J Virol

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“…Due to the oncogenic potential of these viruses, viral proteins targeting p53 were generally thought to have a role in tumorigenesis. However, viruses without tumorigenic potential, such as vaccinia virus (VV), have also been shown to encode proteins that can target p53 (32). Moreover, p53 KO mice, in contrast to wildtype (WT) mice, are highly sensitive to vesicular stomatitis virus (VSV) infection (38).…”

mentioning

confidence: 99%

Down-Regulation of p53 by Double-Stranded RNA Modulates the Antiviral Response

Marques¹,

Rebouillat²,

Ramana

et al. 2005

J Virol

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p53 has been well characterized as a tumor suppressor gene, but its role in antiviral defense remains unclear. A recent report has demonstrated that p53 can be induced by interferons and is activated after vesicular stomatitis virus (VSV) infection. We observed that different nononcogenic viruses, including encephalomyocarditis virus (EMCV) and human parainfluenza virus type 3 (HPIV3), induced down-regulation of p53 in infected cells. Double-stranded RNA (dsRNA) and a mutant vaccinia virus lacking the dsRNA binding protein E3L can also induce this effect, indicating that dsRNA formed during viral infection is likely the trigger for down-regulation of p53. The mechanism of down-regulation of p53 by dsRNA relies on translation inhibition mediated by the PKR and RNase L pathways. In the absence of p53, the replication of both EMCV and HPIV3 was retarded, whereas, conversely, VSV replication was enhanced. Cell cycle analysis indicated that wild-type (WT) but not p53 knockout (KO) fibroblasts undergo an early-G 1 arrest following dsRNA treatment. Moreover, in WT cells the onset of dsRNA-induced apoptosis begins after p53 levels are down-regulated, whereas p53 KO cells, which lack the early-G 1 arrest, rapidly undergo apoptosis. Hence, our data suggest that the down-regulation of p53 facilitates apoptosis, thereby limiting viral replication.

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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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The vaccinia virus B1R kinase induces p53 downregulation by an Mdm2-dependent mechanism

Cited by 44 publications

References 50 publications

Vaccinia Virus B1R Kinase Interacts with JIP1 and Modulates c-Jun-Dependent Signaling

Vaccinia Virus B1R Kinase Interacts with JIP1 and Modulates c-Jun-Dependent Signaling

Down-Regulation of p53 by Double-Stranded RNA Modulates the Antiviral Response

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

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