Aggregatibacter actinomycetemcomitans Cytolethal Distending Toxin-Induces Cell Cycle Arrest in a Glycogen Synthase Kinase (GSK)-3-Dependent Manner in Oral Keratinocytes.
Aggregatibacter actinomycetemcomitans Cytolethal Distending Toxin-Induces Cell Cycle Arrest in a Glycogen Synthase Kinase (GSK)-3-Dependent Manner in Oral Keratinocytes.
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DOI：
10.3390/ijms231911831
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发表时间：
2022-10-05
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
--
作者：
细胞致死性膨胀毒素（Cdt）是由多种病原体产生的。一种产生Cdt的生物体，伴放线菌聚集杆菌，在一种独特形式的牙周炎（以前称为局部侵袭性牙周炎）的发病机制中起着关键作用。活性Cdt亚基CdtB是一种有效的磷脂酰肌醇（PI）3，4，5-三磷酸酶，能够诱导PI-3-激酶信号传导阻断，这是淋巴细胞中Cdt诱导毒性的必要条件。在这项研究中，我们扩大了我们的观察，包括口腔角质形成细胞对AaCdt的反应，使用细胞系和原代牙龈角质形成细胞。当暴露于AaCdt毒素24 h内，所有三种都表现出G2/M期阻滞。毒素处理的细胞在6 h内表现出pAkt和pGSK 3 β水平降低。GSK 3 β激酶抑制剂LY 2090314、CHIR 99021和Tideglusib可阻断Cdt诱导的G2/M期阻滞。没有口腔上皮细胞表现出凋亡的证据。细胞保持停滞在G2/M期至少72小时，没有DNA损伤应答激活（H2 AX磷酸化）的证据。Cdt处理的细胞显示细胞周期蛋白依赖性激酶1（CDK 1）磷酸化增加;此外，GSK 3抑制剂阻断了这种增加并降低了总CDK 1水平。本研究进一步阐明了导致Cdt毒性和毒素介导的发病机制的潜在机制。
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 pGSK3β within 6 h. Pre-treatment with GSK3β 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.
影响因子：
3.7
作者：
Alaoui-El-Azher M;Mans JJ;Baker HV;Chen C;Progulske-Fox A;Lamont RJ;Handfield M
通讯作者：
Handfield M
影响因子：
6.7
作者：
Nesic D;Stebbins CE
通讯作者：
Stebbins CE
影响因子：
3.7
作者：
Guerra L;Albihn A;Tronnersjö S;Yan Q;Guidi R;Stenerlöw B;Sterzenbach T;Josenhans C;Fox JG;Schauer DB;Thelestam M;Larsson LG;Henriksson M;Frisan T
通讯作者：
Frisan T