Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 23, Issue 19, Pages -Publisher
MDPI
DOI: 10.3390/ijms231911831
Keywords
cytolethal distending toxin; Aggregatibacter actinomycetemcomitans; cell cycle arrest; GSK3; apoptosis; DNA damage response; epithelial cells
Funding
- National Institute of Dental and Craniofacial Research at the National Institutes of Health [DE006014, DE023071]
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In this study, the researchers investigated the mechanism of Cdt-induced periodontitis by using cell lines and primary gingival keratinocytes. The findings showed that Cdt caused G2/M arrest in cells and reduced levels of pAkt and pGSK3 beta. Pre-treatment with GSK3 beta kinase inhibitors reversed the G2/M arrest caused by Cdt. Furthermore, Cdt-treated cells displayed increased phosphorylation of CDK1, which was blocked by GSK3 inhibitors and resulted in reduced total CDK1 levels. This study provides further insights into the potential mechanism(s) contributing to Cdt toxicity and toxin-mediated pathogenesis in periodontitis.
Cytolethal distending toxins (Cdt) are produced by a diverse group of pathogens. One Cdt-producing organism, Aggregatibacter actinomycetemcomitans, plays a critical role in the pathogenesis of a unique form of periodontitis, formerly referred to as localized aggressive periodontitis. The active Cdt subunit, CdtB, is a potent phosphatidylinositol (PI) 3,4,5-triphosphate phosphatase capable of inducing PI-3-kinase signaling blockade, a requisite for Cdt-induced toxicity in lymphocytes. In this study, we extended our observations to include the oral keratinocyte response to AaCdt using cell lines and primary gingival keratinocytes. All three exhibited G2/M arrest when exposed to AaCdt toxin within 24 h. Toxin-treated cells exhibited reduced levels of pAkt and pGSK3 beta within 6 h. Pre-treatment with GSK3 beta kinase inhibitors, LY2090314, CHIR99021 and Tideglusib, abrogated Cdt-induced G2/M arrest. None of the oral epithelial cells exhibited evidence of apoptosis. Cells remained arrested in the G2/M phase for at least 72 h without evidence of DNA damage response activation (H2AX phosphorylation). Cdt-treated cells displayed increased phosphorylation of the cyclin dependent kinase 1 (CDK1); moreover, the GSK3 inhibitors blocked this increase and reduced total CDK1 levels. This study further clarifies the potential mechanism(s) contributing to Cdt toxicity and toxin-mediated pathogenesis.
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