Polyomavirus hr-t mutant-specific induction of a G2/M cell-cycle arrest that is not overcome by the expression of middle T and/or small T

Spink, Kathryn M.; Fluck, Michele M.

doi:10.1016/s0042-6822(02)00030-2

Cited by 5 publications

(10 citation statements)

References 27 publications

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“…Yeast cells were able to overcome the block by assembly of a new spindle [57]. The association between VP1 and cell cycle arrest was also postulated by Spink and Fluck [60]. It was suggested that such VP1producing cells may be important in the development of aneuploidy in tumors [58].…”

Section: Discussionmentioning

confidence: 85%

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VP1, the major capsid protein of the mouse polyomavirus, binds microtubules, promotes their acetylation and blocks the host cell cycle

et al. 2017

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VP1, the major structural protein of the mouse polyomavirus (MPyV), is the major architectural component of the viral capsid. Its pentamers are able to self-assemble into capsid-like particles and to non-specifically bind DNA. Surface loops of the protein interact with sialic acid of ganglioside receptors. Although the replication cycle of the virus, including virion morphogenesis, proceeds in the cell nucleus, a substantial fraction of the protein is detected in the cytoplasm of late-phase MPyV-infected cells. In this work, we detected VP1 mainly in the cytoplasm of mammalian cells transfected with plasmid expressing VP1. In the cytoplasm, VP1-bound microtubules, including the mitotic spindle, and the interaction of VP1 with microtubules resulted in cell cycle block at the G2/M phase. Furthermore, in the late phase of MPyV infection and in cells expressing VP1, microtubules were found to be hyperacetylated. We then sought to understand how VP1 interacts with microtubules. Dynein is not responsible for the VP1-microtubule association, as neither overexpression of p53/dynamitin nor treatment with ciliobrevin-D (an inhibitor of dynein activity) prevented binding of VP1 to microtubules. A pull-down assay for VP1-interacting proteins identified the heat shock protein 90 (Hsp90) chaperone, and Hsp90 was also detected in the VP1-microtubule complexes. Although Hsp90 is known to be associated with acetylated microtubules, it does not mediate the interaction between VP1 and microtubules. Our study provides insight into the role of the major structural protein in MPyV replication, indicating that VP1 is a multifunctional protein that participates in the regulation of cell cycle progression in MPyV-infected cells.

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Section: Discussionmentioning

confidence: 85%

“…VP1 was also found to interact with microtubules and spindle bodies in early MPyV-induced epithelial tumors where VP1 was expressed. Most of the cells from the infected cell population exhibited block in the first G2/M phase of the cell cycle [60]. Later in tumor progression, the VP1 gene was found to be silenced [59].…”

Section: Discussionmentioning

confidence: 99%

VP1, the major capsid protein of the mouse polyomavirus, binds microtubules, promotes their acetylation and blocks the host cell cycle

et al. 2017

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“…A common feature of many viral infections is the subversion of the host cellular cycle to create an intracellular environment suitable for maximized viral DNA replication (Ben-Israel and Kleinberger, 2002; Spink and Fluck, 2003; Chen and Qiu, 2010; Sakai et al, 2011; Li et al, 2012). Very diverse strategies have been developed by viruses, from the stimulation of cell cycle progression in quiescent cells, to blockade of cell cycle progression in proliferating ones (Op De Beeck and Caillet-Fauquet, 1997; Davy and Doorbar, 2007).…”

Section: Baculovirus Infection: Impact On the Host Cellmentioning

confidence: 99%

Toward system-level understanding of baculovirus–host cell interactions: from molecular fundamental studies to large-scale proteomics approaches

Monteiro¹,

Carinhas²,

Carrondo³

et al. 2012

Front. Microbio.

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Baculoviruses are insect viruses extensively exploited as eukaryotic protein expression vectors. Molecular biology studies have provided exciting discoveries on virus–host interactions, but the application of omic high-throughput techniques on the baculovirus–insect cell system has been hampered by the lack of host genome sequencing. While a broader, systems-level analysis of biological responses to infection is urgently needed, recent advances on proteomic studies have yielded new insights on the impact of infection on the host cell. These works are reviewed and critically assessed in the light of current biological knowledge of the molecular biology of baculoviruses and insect cells.

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“…This has been investigated with various wild-type and mutant strains of virus in both permissive mouse cells and nonpermissive rat cells (29,43,47). Earlier studies have also shown that the adult mouse kidney, which is normally nonpermissive, becomes permissive and allows reactivation of persistent infection by polyomavirus following cellular damage induced by glycerol, cisplatin, or hypoxia (2).…”

mentioning

confidence: 99%

Induction and Utilization of an ATM Signaling Pathway by Polyomavirus

Dahl

You

Benjamin

2005

J Virol

112

125

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Progression from G 1 to S is essential for polyomavirus DNA replication and depends on the interaction of large T with the retinoblastoma gene product pRb. This virus-induced replication pathway is accompanied by p53 activation resembling a DNA damage response (12). We sought to determine whether this pathway depends in part on activation of the ATM (ataxia telangiectasia mutated) kinase and whether the virus gains advantages from this pathway beyond that of entry into S. We show that polyomavirus infection activates the S-and G 2 -phase checkpoints in primary as well as established mouse cells. Infected cells undergo a prolonged S phase compared to uninfected serum-stimulated cells and show no evidence of a G 2 3M transition before lytic death ensues. Infection is accompanied by increases in ATM activity in vitro and in the level of ATM-S1981-P in vivo. The incubation of infected cells with caffeine, a known ATM inhibitor, did not block entry into S but reduced the rate of viral compared to cellular DNA synthesis. Importantly, caffeine lowered the yields of viral DNA an average of 3-to 6-fold and those of infectious virus by as much as 10-fold. Virus yields were 10-fold lower in ATM ؊/؊ p53 ؊/؊ than in ATM ؉/؉ p53 ؊/؊ mouse embryo fibroblasts, indicating a p53-independent role of ATM in productive infection. Replacement of the normal SMC1 (structural maintenance of chromosomes, or cohesin) protein, a critical ATM substrate in the DNA repair pathway, with its phosphorylation mutant SMC1 S957AS966A also lowered virus yields by roughly 90%. We suggest that polyomavirus activates and utilizes a component(s) of an ATM pathway of DNA repair to prolong S phase and aid its own replication.A productive infection by polyomavirus is accompanied by activation as well as inactivation of tumor suppressor gene pathways. A critical event is the interaction of the large T antigen with pRb, the product of the retinoblastoma tumor suppressor gene. This interaction leads to an override of the G 1 checkpoint and the entry of cells into S, thus allowing viral DNA synthesis to occur (17). A productive infection by polyomavirus also results in the induction of p53 and a DNA damage-like response. Interestingly, this induction also depends on a large T-pRb interaction, based presumably on E2F activation and the assembly of initiation complexes on viral DNA with the formation of theta structures (12). The p53 response, although accompanied by the induction of p21 CIP1/WAF1 (p21), does not lead to G 1 arrest because of the downstream intervention at the pRb checkpoint by large T. The viral replication pathway leading to p53 induction may impose additional events on the infected cell beyond those of entry into S and raises questions about the possible utilization of a DNA damage response-like pathway by the virus.Previous studies have shown that cells infected by polyomavirus accumulate in S and G 2 phase. This has been investigated with various wild-type and mutant strains of virus in both permissive mouse cells and nonpermissive rat cell...

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Polyomavirus hr-t mutant-specific induction of a G2/M cell-cycle arrest that is not overcome by the expression of middle T and/or small T

Cited by 5 publications

References 27 publications

VP1, the major capsid protein of the mouse polyomavirus, binds microtubules, promotes their acetylation and blocks the host cell cycle

VP1, the major capsid protein of the mouse polyomavirus, binds microtubules, promotes their acetylation and blocks the host cell cycle

Toward system-level understanding of baculovirus–host cell interactions: from molecular fundamental studies to large-scale proteomics approaches

Induction and Utilization of an ATM Signaling Pathway by Polyomavirus

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