Journal Article

Essential roles of PI-3K/Akt/IKKβ/NFκB pathway in cyclin D1 induction by arsenite in JB6 Cl41 cells

Weiming Ouyang, Jingxia Li, Qian Ma and Chuanshu Huang

in Carcinogenesis

Volume 27, issue 4, pages 864-873
Published in print April 2006 | ISSN: 0143-3334
Published online December 2005 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgi321
Essential roles of PI-3K/Akt/IKKβ/NFκB pathway in cyclin D1 induction by arsenite in JB6 Cl41 cells

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Skin is a major target of carcinogenic trivalent arsenic (arsenite, As3+). It has been thought that cell proliferation is one of the central events involved in the carcinogenic effect of arsenite. Cyclin D1, a nuclear protein playing a pivotal role in cell proliferation and cell cycle transition from G1 to S phases, has been reported to be induced in human fibroblast by arsenite via uncertain molecular mechanisms. In the present study, the potential roles of PI-3K/Akt/IKKβ/NFκB signal pathway in cyclin D1 induction by arsenite were addressed in mouse epidermal Cl41 cells. We found that exposure of Cl41 cells to arsenite was able to induce cell proliferation, activate PI-3K→Akt/p70S6k signal pathway and increase cyclin D1 expression at both transcription and protein levels. Pre-treatment of Cl41 cells with PI-3K inhibitor, wortmannin, significantly inhibited the phosphorylation of Akt and p70S6k and thereby dramatically impaired the cyclin D1 induction by arsenite, implicating the importance of the PI-3K signal pathway in the cyclin D1 induction by arsenite. Furthermore, inhibition of PI-3K/Akt by overexpression of Δp85 or DN-Akt blocked arsenite-induced IKK phosphorylation, IκBα degradation and cyclin D1 expression, indicating that IKK/NFκB is the downstream transducer of arsenite-triggered PI-3K/Akt cascade. Moreover, inhibition of IKKβ/NFκB signal pathway by overexpression of its dominant negative mutant, IKKβ-KM, also significantly blocked arsenite-induced cyclin D1 expression. Overall, arsenite exposure triggered PI-3K/Akt/IKKβ/NFκB signal cascade which in turn plays essential roles in inducing cyclin D1 expression.

Keywords: APC, human adenomatous polyposis coli gene; CDKs, cyclin-dependent kinases; DMSO, dimethyl sulfoxide; ERK, extracellular signal-regulated kinase; FBS, fetal bovine serum; GSK3β, glycogen synthase kinase-3β; IKK, IκB kinase; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; MEM, Eagle's minimal essential medium; mTOR, mammalian target of rapamycin; NFκB, nuclear factor-κB; PI-3K, phosphotidylinositol-3 kinase; PKCα, protein kinase Cα.

Journal Article.  7387 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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