Cytolethal Distending Toxin: A Unique Variation on the AB Toxin Paradigm
Figure 4
CdtB-induced inhibitory pathways. (a) Schematic representation of stages in the cell cycle showing the locations of the G1 and G2 DNA damage checkpoints. (b) Cell cycle arrest at G2/M can be measured by flow cytometry or cell sorting. Populations that are arrested at G2/M accumulate cells that have a 4 DNA content. (c) Normal cell cycle pathway leading to mitosis. Protein kinases Myt1 and Wee1 phosphorylate the effector kinase Cdc2/Cdk1 which forms a complex with cyclin B. The complex is activated by the removal of phosphate by the protein phosphatase Cdc25 allowing the cells to enter mitosis. (d) Cdt-induced DNA damage resulting in arrest at either the G1 or G2 checkpoint. DNA damage sensor proteins are recruited to the repair site depending on the cell type either the ataxia telangiectasia mutated/ATM and Rad3-related (ATR/ATM) or p53 pathway is initiated. Arrest at the G1 phase of the cell cycle occurs when the phosphorylated tumor suppressor protein p53 complex mediates the upregulation of p21 which inactivates a Cdc2-cyclin E complex and the proliferating cell nuclear antigen (PCNA). Cdt-induced DNA damage can also trigger a response by the DNA damage sensor proteins leading to activation of the ATM and ATR checkpoint pathways. In these pathways the effector kinases Chk1 and Chk2 phosphorylate, and therefore inactivate Cdc25. Activation of the ATM pathway can also lead to the initiation of a survival pathway in which the ATM protein kinase dephosphorylates the neuroepithelioma transforming protein, Net1, which activates RhoA which in turn activates the RhoA activated kinases (ROCK). (e) Putative pathway by which CdtB may affect the phosphatidylinositol-3-kinase (PIK3) signaling pathway and the production of proinflammatory or anti-inflammatory cytokines. CdtB may function as a phosphatidylinositol-3,4,5-triphosphate 3-phosphatase (PTEN) that removes a phosphate group from phosphatidylinositol-3,4,5-triphosphate (PIP3) present in the plasma membrane. This depletion of PIP3 in lymphocytes inactivates the Akt pathway leading to cell cycle arrest and apoptosis. In macrophages, PIK3 may be activated by toll-like receptors (TLRs) in the cell membrane resulting in the synthesis of PIP3 and the activation of Akt. This activator of anabolic signaling pathways acts on the glycogen synthase kinase-3 (GSK3β). GSK3β and phosphorylated GSK3β direct the pathway toward the synthesis of proinflammatory and anti-inflammatory cytokines, respectively. The mTOR (mammalian target of rapamycin) protein complex is also regulated by the Akt kinase and participates in the control of protein synthesis and cell growth. Additional details are provided in the text. CBP: CREB-binding protein; CREB: cAMP response element binding protein; TLR: toll-like receptor. The pathways were compiled and modified from those described in other studies [89, 90, 95, 119, 177, 212].
