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Infection and Immunity, February 2002, p. 528-534, Vol. 70, No. 2
0019-9567/01/$04.00+0     DOI: 10.1128/IAI.70.2.528-534.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

p53-Independent Expression of p21CIP1/WAF1 in Plasmacytic Cells during G2 Cell Cycle Arrest Induced by Actinobacillus actinomycetemcomitans Cytolethal Distending Toxin

Tsuyoshi Sato,1,2 Takeyoshi Koseki,1 Kenji Yamato,3 Keitarou Saiki,4 Kiyoshi Konishi,4 Masanosuke Yoshikawa,4 Isao Ishikawa,2 and Tatsuji Nishihara5*

Department of Oral Science, National Institute of Infectious Diseases, Tokyo 162-8640,1 Periodontology,2 Molecular Cellular Oncology and Microbiology, Tokyo Medical and Dental University, Tokyo 113-8549,3 Department of Microbiology, Nippon Dental University, Tokyo 102-8159,4 Department of Oral Microbiology, Kyushu Dental College, Kitakyushu, Fukuoka 803-8580, Japan5

Received 28 June 2001/ Returned for modification 21 September 2001/ Accepted 16 October 2001

The cytolethal distending toxin (CDT) from Actinobacillus actinomycetemcomitans has been shown to induce cell cycle arrest in the G2/M phase in HeLa cells. In the present study, the mechanism of CDT-induced cell cycle arrest was investigated by using HS-72 cells, a murine B-cell hybridoma cell line. Using flow cytometric analysis, we found that the recombinant CDT (rCDT) from A. actinomycetemcomitans induced G2 cell cycle arrest in HS-72 cells and that rCDT upregulated expression of the cyclin-dependent kinase inhibitor p21CIP1/WAF1 and the tumor suppressor protein p53. HS-72 cells transfected with the E6/E7 gene of human papillomavirus type 16, which lacked rCDT-induced accumulation of p53, exhibited expression of p21CIP1/WAF1 or G2 cell cycle arrest upon exposure to rCDT. Furthermore, ectopic expression of a dominant negative p53 mutant did not inhibit rCDT-mediated p21CIP1/WAF1 expression or G2 cell cycle arrest in HS-72 cells. These results suggest that the CDT from A. actinomycetemcomitans induces p21CIP1/WAF1 expression and G2 cell cycle arrest in B-lineage cells by p53-independent pathways. Together with additional observations made with HeLa cells and COS-1 cells cultured with the rCDT from A. actinomycetemcomitans, the results of this study indicate that CDT-induced p53 accumulation may not be required for G2 cell cycle arrest and that an increased level of p21CIP1/WAF1 may be important for sustaining G2 cell cycle arrest in several mammalian cells.

* Corresponding author. Mailing address: Department of Oral Microbiology, Kyushu Dental College, 2-6-1 Manazuru, Kokurakita-ku, Kitakyushu 803-8580, Japan. Phone: 81-93-582-1131, ext. 5485. Fax: 81-93-581-4984. E-mail: tatsujin{at}kyu-dent.ac.jp.

Editor: E. I. Tuomanen

Infection and Immunity, February 2002, p. 528-534, Vol. 70, No. 2
0019-9567/01/$04.00+0     DOI: 10.1128/IAI.70.2.528-534.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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