The bacterial cytolethal distending toxin (CDT) triggers a G2 cell cycle checkpoint in mammalian cells without preliminary induction of DNA strand breaks

Sert, V; Cans, Christophe; Tasca, Christian; Bret-Bennis, Lydie; Oswald, Éric; Ducommun, Bernard; Rycke, Jean de

doi:10.1038/sj.onc.1203007

Cited by 72 publications

(111 citation statements)

References 33 publications

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“…The strategy was to investigate the early events occurring in intoxicated cells and compare the effects caused by HdCDT with those induced by ionizing radiation. This is the first report where CDT-intoxicated cells have been analyzed at short time points after toxin exposure, whereas all previous studies have been performed mainly at 24 or 72 h post-intoxication (2,24,28,29). Furthermore, we have tested a broad panel of human cell types, including normal keratinocytes and fibroblasts, which are conceivable toxin targets in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…Activation of chk2 can lead to cdc25C inactivation and accumulation of hyperphosphorylated cdc2. Indeed, inactivation of cdc25C was previously demonstrated in HeLa cells treated with the Escherichia coli CDT (29), and overexpression of cdc25B and cdc25C could prevent cell intoxication (31).…”

Section: Figmentioning

confidence: 99%

“…Sert and colleagues (29) did not detect DNA strand breaks in cells intoxicated with a CDT derived from E. coli, using the single cell gel electrophoresis assay ("comet assay"). However, two recent reports have demonstrated that cdtB from E. coli and Campylobacter jejuni has structural and functional homology to the mammalian type I DNase.…”

Section: Figmentioning

confidence: 99%

“…3, A and B, and Ref. 29). Recent studies have demonstrated that caffeine abolishes the G 2 block in mammalian cells upon DNA damage by inhibiting the activation of the ATM kinase and consequently blocking the downstream activation of the chk2 protein (26,27).…”

Section: Figmentioning

confidence: 99%

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The Haemophilus ducreyi Cytolethal Distending Toxin Induces Cell Cycle Arrest and Apoptosis via the DNA Damage Checkpoint Pathways

Cortes-Bratti¹,

Karlsson²,

Lagergård³

et al. 2001

Journal of Biological Chemistry

147

173

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The cytolethal distending toxins (CDTs) induce cell cycle arrest by a mechanism still not well characterized. We demonstrate that the effect of the Haemophilus ducreyi CDT (HdCDT) is cell type-specific: B cell lines underwent apoptosis, epithelial cells and keratinocytes arrested exclusively in G 2 , whereas normal fibroblasts arrested both in G 1 and G 2 . We studied normal keratinocytes and fibroblasts, which are relevant for understanding the pathogenicity of H. ducreyi. The response to HdCDT resembles the checkpoint response activated by ionizing radiation. Both responses were characterized by an early induction of the p53 gene and the cyclindependent kinase inhibitor p21 in fibroblasts, and activation of the chk2 kinase in epithelial cells. In the Ataxia Telangiectasia-mutated gene (ATM)-deficient lymphoblastoid cell lines, intoxication was significantly delayed compared with ATM wild type cells, and was associated with a slower kinetic of p53 stabilization, suggesting that the early response to HdCDT is ATM-dependent. Activation of ATM-dependent pathways was further confirmed by the ability of caffeine to partially override the HdCDT-mediated cell cycle arrest. Our data shed new light on the mechanism of action of this novel family of bacterial toxins, limiting the target candidates to DNA or molecules directly involved in activation of checkpoint responses.

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Section: Discussionmentioning

confidence: 99%

Section: Figmentioning

confidence: 99%

Section: Figmentioning

confidence: 99%

Section: Figmentioning

confidence: 99%

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The Haemophilus ducreyi Cytolethal Distending Toxin Induces Cell Cycle Arrest and Apoptosis via the DNA Damage Checkpoint Pathways

Cortes-Bratti¹,

Karlsson²,

Lagergård³

et al. 2001

Journal of Biological Chemistry

147

173

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“…HeLa cells were transfected using Exgen-500 (Euromedex) following the manufacturer's instructions. Cell cycle synchronization was achieved as described previously (28). The U2OS cell line conditionally expressing hemagglutinin (HA)-tagged CDC25B1 (under the control of the tet-promoter) is described previously (29).…”

Section: Methodsmentioning

confidence: 99%

A Novel Synthetic Inhibitor of CDC25 Phosphatases

et al. 2004

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CDC25 dual-specificity phosphatases are essential regulators that dephosphorylate and activate cyclin-dependent kinase/cyclin complexes at key transitions of the cell cycle. CDC25 activity is currently considered to be an interesting target for the development of new antiproliferative agents. Here we report the identification of a new CDC25 inhibitor and the characterization of its effects at the molecular and cellular levels, and in animal models.BN82002 inhibits the phosphatase activity of recombinant human CDC25A, B, and C in vitro. It impairs the proliferation of tumoral cell lines and increases cyclin-dependent kinase 1 inhibitory tyrosine phosphorylation. In synchronized HeLa cells, BN82002 delays cell cycle progression at G 1 -S, in S phase and at the G 2 -M transition. In contrast, BN82002 arrests U2OS cell cycle mostly in the G 1 phase. Selectivity of this inhibitor is demonstrated: (a) by the reversion of the mitotic-inducing effect observed in HeLa cells upon CDC25B overexpression; and (b) by the partial reversion of cell cycle arrest in U2OS expressing CDC25. We also show that BN82002 reduces growth rate of human tumor xenografts in athymic nude mice.BN82002 is a original CDC25 inhibitor that is active both in cell and animal models. This greatly reinforces the interest in CDC25 as an anticancer target.

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The struggle within: Microbial influences on colorectal cancer

Arthur

Jobin

2011

Inflammatory Bowel Diseases

108

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Recently, an unprecedented effort has been directed at understanding the interplay between chronic inflammation and development of cancer, with the case of inflammatory bowel disease (IBD)-associated colorectal cancer at the forefront of this research endeavor. The last decade has been particularly fertile, with the discovery of numerous innovative paradigms linking various inflammatory, proliferative, and innate and adaptive immune signaling pathways to the development of colorectal cancer. Because of the preponderant role of the intestinal microbiota in the initiation and progression of IBD, recent efforts have been directed at understanding the relationship between bacteria and colorectal cancer. The microbiota and its collective genome, the microbiome, form a diverse and complex ecological community that profoundly impacts intestinal homeostasis and disease states. This review will discuss the differential influence of the microbiota on the development of IBD-associated colorectal cancer and highlight the role of innate immune sensor-dependent as well as -independent mechanisms in this pathology.

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The bacterial cytolethal distending toxin (CDT) triggers a G2 cell cycle checkpoint in mammalian cells without preliminary induction of DNA strand breaks

Cited by 72 publications

References 33 publications

The Haemophilus ducreyi Cytolethal Distending Toxin Induces Cell Cycle Arrest and Apoptosis via the DNA Damage Checkpoint Pathways

The Haemophilus ducreyi Cytolethal Distending Toxin Induces Cell Cycle Arrest and Apoptosis via the DNA Damage Checkpoint Pathways

A Novel Synthetic Inhibitor of CDC25 Phosphatases

The struggle within: Microbial influences on colorectal cancer

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