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Cyclin D1 Induction through IB Kinase ß/Nuclear Factor-B Pathway Is Responsible for Arsenite-Induced Increased Cell Cycle G₁-S Phase Transition in Human Keratinocytes

Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York

Requests for reprints: Chuanshu Huang, Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987. Phone: 845-731-3519; Fax: 845-351-2320; E-mail: chuanshu{at}env.med.nyu.edu.

Environmental and occupational exposure to arsenite is associated with an increased risk of human cancers, including skin, urinary bladder, and respiratory tract cancers. Although much evidence suggests that alterations in cell cycle machinery are implicated in the carcinogenic effect of arsenite, the molecular mechanisms underlying the cell cycle alterations are largely unknown. In the present study, we observed that exposure of human keratinocyte HaCat cells to arsenite resulted in the promotion of cell cycle progression, especially G₁-S transition. Further studies found that arsenite exposure was able to induce cyclin D1 expression. The induction of cyclin D1 by arsenite required nuclear factor-B (NF-B) activation, because the inhibition of IB phosphorylation by overexpression of the dominant-negative mutant, IKKß-KM, impaired arsenite-induced cyclin D1 expression and G₁-S transition. The requirement of IB kinase ß (IKKß) for cyclin D1 induction was further confirmed by the findings that arsenite-induced cyclin D1 expression was totally blocked in IKKß knockout (IKKß^–/–) mouse embryo fibroblasts. In addition, knockdown of cyclin D1 expression using cyclin D1–specific small interference RNA significantly blocked arsenite-induced cell cycle progression in HaCat cells. Taken together, our results show that arsenite-induced cell cycle from G₁ to S phase transition is through IKKß/NF-B/cyclin D1–dependent pathway.

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