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  • Benzo[a]pyrene, but not 2,3,7,8-TCDD, induces G2/M cell cycle arrest, p21CIP1 and p53 phosphorylation in human choriocarcinoma JEG-3 cells: a distinct signaling pathway.

Benzo[a]pyrene, but not 2,3,7,8-TCDD, induces G2/M cell cycle arrest, p21CIP1 and p53 phosphorylation in human choriocarcinoma JEG-3 cells: a distinct signaling pathway.

Placenta (2005-04-20)
J S Drukteinis, T Medrano, E A Ablordeppey, J M Kitzman, K T Shiverick
ABSTRACT

Maternal cigarette smoking is known to disrupt placental growth and function. The polyaromatic hydrocarbon benzo[a]pyrene (BaP) is a major toxicant in cigarette smoke that has been shown to alter placental cell function. This study compared the effects of the benzo[a]pyrene (BaP) with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the prototype ligand for the aryl hydrocarbon (Ah) receptor, on proliferation and cell cycle progression in the human trophoblastic JEG-3 cell line. BaP, but not TCDD, significantly inhibited proliferation in a dose-dependent manner characterized by G2/M cell cycle phase arrest. No evidence of apoptosis was detected following BaP or TCDD exposure. Immunocytochemistry and Western blot analysis showed that BaP induced expression of nuclear p21CIP1 protein, the major inhibitor of cyclin-dependent kinases. In contrast, CDK1 expression, the main G2 cyclin-dependent kinase, was significantly reduced by 50% with a shift in localization from the nucleus to cytoplasm. Although BaP had no effect on total cellular p53 levels, phosphorylation of p53 at serine 15 (p53 ser-15phos) was markedly increased. The presence of Wortmannin, an inhibitor of PI-3 kinases, decreased BaP-induced p53 ser-15phos, as did the presence of the antioxidant vitamin E. In addition, vitamin E suppressed BaP-induced G2/M arrest without altering the level of induced CYP1A1 protein. Thus, the anti-proliferative effect of BaP involves activation of a p53-dependent pathway involving cell cycle arrest at G2/M, providing evidence of oxidative stress and activation of a DNA damage response pathway in JEG-3 cells.

MATERIALS
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Sigma-Aldrich
D-α-Tocopherol succinate, semisynthetic, 1210 IU/g

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