Soluble and insoluble nickel compounds exert a differential inhibitory effect on cell growth through IKKalpha-dependent cyclin D1 down-regulation.
It is well-known that insoluble nickel compounds possess much more potent carcinogenic activities as compared with soluble nickel compounds. Although it is assumed that the different entry and clearance rate are responsible for the difference, the mechanisms underlying the different carcinogenic activities are still not well understood yet. In the present study, we found that exposure to soluble, but not insoluble nickel compounds, caused a significant inhibition of cell growth and G1/G0 cell cycle arrest, which was concomitant with a marked down-regulation of cylin D1, an essential nuclear protein for controlling G1/S transition, while both soluble and insoluble nickel compounds showed similar effects on NFkappaB activation, HIF-1alpha protein accumulation and TNF-alpha transcription and CAP43 protein expression at same doses range. The down-regulation of cyclin D1 is due to protein degradation rather than inhibition of transcription, because the nickel compounds treatment did not change cyclin D1 mRNA level, while MG132, the proteasome inhibitor, can rescue the degradation of cyclin D1 caused by soluble nickel compound. Moreover, the soluble nickel-induced cyclin D1 degradation is dependent on its Thr286 residue and requires IKKalpha, but not HIF-1alpha, which are both reported to be involved in cyclin D1 down-regulation. Taken together, we demonstrate that soluble, but not insoluble nickel compound, is able to cause cyclin D1 degradation and a cell growth arrest in an IKKalpha-dependent manner. Given the role of cyclin D1 and cell proliferation in carcinogenesis, we anticipate that the different effects of soluble and insoluble nickel compounds on cyclin D1 degradation and cell growth arrest may at least partially account for their different carcinogenic activities.
Ouyang
Weiming
W
Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York, USA.
Zhang
Dongyun
D
Li
Jingxia
J
Verma
Udit N
UN
Costa
Max
M
Huang
Chuanshu
C
D000818:Animals; D001483:Base Sequence; D002273:Carcinogens / Q000633:toxicity; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051550:I-kappa B Kinase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009532:Nickel / Q000633:toxicity*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012995:Solubility
C530104:CCND1 protein, human; D002273:Carcinogens; C530105:Ccnd1 protein, mouse; D017931:DNA Primers; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D019938:Cyclin D1; C022838:nickel chloride; D009532:Nickel; C496559:CHUK protein, human; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C017558:nickel sulfide; C017557:nickel subsulfide
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