Analysis of mechanism of the induction of apoptosis induced by the toxin derived form periodontopathic bacteria and its intracellular signal transduction

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The cytolethal distending toxin (CDT) from Actinobacillus actinomycetemcomitans was previously shown to induce cell cycle arrest in G2/M phase in Hela cells. In the present study, we demonstrated that the CDT from A.actinomycetemcomitans induced G2 cell cycle arrest in the B cell hybridoma cell line, HS-72 by flow cytometric analysis. The mechanism of CDT-induced cell cycle arrest was investigated using HS-72 cells. The CDT up-regulated the expression of cyclin-dependent kinase inhibitor p21CIP1/WAF1 and tumor-suppressor protein p53. The ectopic expression of human papilloma virus type-16 E6/E7 abolished the CDT-induced expression of p53. However, E6/E7 expression had no effect on the expression of p21CIP1/WAF1 and G2 cell cycle arrest in HS-72 cells cultured with the CDT.Furthermore, overexpression of adominant negative p53 mutant did not inhibit the CDT-mediated p21CIP1/WAF1 expression and G2 cell cycle arrest in HS-72 cells. These results indicate that the CDT from A.actinomycetemcomitans induce p21CIP1/WAF1 expression and G2 cell cycle arrest in B lineage cells by p53-independent pathways. Together with additional observations on Hela and COS-1 cells cultured with the CDT from A.actinomycetemcomitans, the results in the present study suggest the CDT-induced p21CIP1/WAF1 may promote G2 cell cycle arrest in mammmalian cells.