p53-independent expression of p21(CIP1/WAF1) in plasmacytic cells during G(2) cell cycle arrest induced by Actinobacillus actinomycetemcomitans cytolethal distending toxin.
The cytolethal distending toxin (CDT) from Actinobacillus actinomycetemcomitans has been shown to induce cell cycle arrest in the G(2)/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 G(2) cell cycle arrest in HS-72 cells and that rCDT upregulated expression of the cyclin-dependent kinase inhibitor p21(CIP1/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 p21(CIP1/WAF1) or G(2) cell cycle arrest upon exposure to rCDT. Furthermore, ectopic expression of a dominant negative p53 mutant did not inhibit rCDT-mediated p21(CIP1/WAF1) expression or G(2) cell cycle arrest in HS-72 cells. These results suggest that the CDT from A. actinomycetemcomitans induces p21(CIP1/WAF1) expression and G(2) 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 G(2) cell cycle arrest and that an increased level of p21(CIP1/WAF1) may be important for sustaining G(2) cell cycle arrest in several mammalian cells.
Sato
Tsuyoshi
T
Department of Oral Science, National Institute of Infectious Diseases, Tokyo 162-8640, Japan.
Koseki
Takeyoshi
T
Yamato
Kenji
K
Saiki
Keitarou
K
Konishi
Kiyoshi
K
Yoshikawa
Masanosuke
M
Ishikawa
Isao
I
Nishihara
Tatsuji
T
D016976:Aggregatibacter actinomycetemcomitans; D000818:Animals; D001402:B-Lymphocytes; D001427:Bacterial Toxins / Q000235:genetics / Q000494:pharmacology*; D019556:COS Cells; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002522:Chlorocebus aethiops; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis*; D016195:G2 Phase / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000502:physiology*
D001427:Bacterial Toxins; C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53; C447141:cytolethal distending toxin, Actinobacillus actinomycetemcomitans