2,2',4,6,6'-Pentachlorobiphenyl induces mitotic arrest and p53 activation.
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.
Shin
Kum-Joo
KJ
Department of Life Science, Division of Molecular and Life Sciences, and School of Environmental Science and Engineering, Pohang University of Science and Technology, Pohang 790-784, Kyungbuk, Republic of Korea.
Kim
Sun-Hee
SH
Kim
Dohan
D
Kim
Yun-Hee
YH
Lee
Han-Woong
HW
Chang
Yoon-Seok
YS
Gu
Man-Bock
MB
Ryu
Sung Ho
SH
Suh
Pann-Ghill
PG
D000818:Animals; D016203:CDC2 Protein Kinase; D020552:Comet Assay; D004785:Environmental Pollutants / Q000633:toxicity*; D008156:Luciferases; D051379:Mice; D008938:Mitosis / Q000187:drug effects*; D041681:NIH 3T3 Cells; D011078:Polychlorinated Biphenyls / Q000633:toxicity*; D011123:Polyploidy; D008941:Spindle Apparatus / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D004785:Environmental Pollutants; D016159:Tumor Suppressor Protein p53; D011078:Polychlorinated Biphenyls; D008156:Luciferases; D016203:CDC2 Protein Kinase; C417207:2,2',4,6,6'-pentachlorobiphenyl