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

Shin, Kum-Joo and Kim, Sun-Hee and Kim, Dohan and Kim, Yun-Hee and Lee, Han-Woong and Chang, Yoon-Seok and Gu, Man-Bock and Ryu, Sung Ho and Suh, Pann-Ghill (2004) 2,2′,4,6,6′-Pentachlorobiphenyl Induces Mitotic Arrest and p53 Activation. Toxicological Sciences, 78 (2). pp. 215-221. ISSN 1096-6080. doi:10.1093/toxsci/kfh069.

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Polychlorinated biphenyls (PCBs), a class 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. Taking these findings 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 brings about aneuploidy in p53-deficient tumor cells.

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Additional Information:© 2004 Society of Toxicology. Received November 28, 2003; accepted January 5, 2004. Advance Access publication January 21, 2004. We thank Dr. Yusuf A. Hannun and Dr. Chang-Woo Lee for critical evaluation of the manuscript. This work was supported in part by the Ministry of Health and Welfare Grant (00-PJ1-PG1-CH13-0005) of the Republic of Korea.
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Ministry of Health and Welfare (Korea)00-PJ1-PG1-CH13-0005
Subject Keywords:polychlorinated biphenyl; p53; mitotic arrest; genetic instability
Issue or Number:2
Record Number:CaltechAUTHORS:20110831-100931021
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:25181
Deposited By: Tony Diaz
Deposited On:07 Sep 2011 17:57
Last Modified:09 Nov 2021 16:30

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