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ToxSci Advance Access published online on January 21, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh069
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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Received November 28, 2003; accepted January 5, 2004
© 2004 Society of Toxicology

Environmental Toxicology

2,2',4,6,6'-Pentachlorobiphenyl Induces Mitotic Arrest and p53 Activation

Kum-Joo Shin 1, Sun-Hee Kim 2, Dohan Kim 2, Yun-Hee Kim 2, Han-Woong Lee 3, Yoon-Seok Chang 4, Man-Bock Gu 5, Sung Ho Ryu 2, and Pann-Ghill Suh 2*

1 Department of Life Science, Division of Molecular and Life Sciences, Pohang University of Science and Technology, Pohang 790-784, Kyungbuk; Division of Biology, California Institute of Technology, Pasadena, CA 91125
2 Department of Life Science, Division of Molecular and Life Sciences, Pohang University of Science and Technology, Pohang 790-784, Kyungbuk
3 Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon 440-746
4 School of Environmental Science and Engineering, Pohang University of Science and Technology, Pohang 790-784, Kyungbuk
5 Kwangju Institute of Science and Technology, Oryong-dong, Puk-gu, Kwangju, Republic of Korea

* To whom correspondence should be addressed. E-mail: pgs{at}postech.ac.kr.


  Abstract

Polychlorinated biphenyls (PCBs), one of persistent organic pollutants (POPs), have been considered to be involved in cancers, but the underlying mechanisms are not known well. Various cancers are closely related to genetic alteration, therefore, we investigated the effect of PCBs on genetic stability, through p53, a guardian of genome, in NIH 3T3 fibroblasts. Among several congeners examined, 2,2',4,6,6'-pentachlorobiphenyl (PeCB) specifically activated p53-dependent transcription. It also induced p53 nuclear accumulation, but did not cause DNA strand breakage. On the other hand, cell cycle progression that is closely connected to p53 was affected by 2,2',4,6,6'-PeCB, resulting in mitotic arrest. In the arrested cells, mitotic spindle damage was detected. Moreover, in the absence of functional p53, polyploidy was caused by 2,2',4,6,6'-PeCB. These results imply that 2,2',4,6,6'-PeCB induces mitotic arrest by interfering with mitotic spindle assembly, followed by genetic instability which triggers p53-activating signals to prevent further polyploidization. Taken together, we suggest that 2,2',4,6,6'-PeCB could be involved in cancer development by causing genetic instability through mitotic spindle damage, which bring about aneuploidy in p53-deficient tumor cells.

Key Words: polychlorinated biphenyl, p53, mitotic arrest, genetic instability .


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S.-H. Kim, Y.-H. Kim, K.-J. Shin, Y.-S. Oh, C. S. Lee, K.-O. Kang, S. H. Ryu, and P.-G. Suh
2,2',4,6,6'-Pentachlorobiphenyl-Induced Apoptosis Is Limited by Cyclooxygenase-2 Induction
Toxicol. Sci., February 1, 2005; 83(2): 397 - 404.
[Abstract] [Full Text] [PDF]


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