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Effects of nickel on cyclin expression, cell cycle progression and cell proliferation in human pulmonary cells.

ABSTRACT: Frequent exposure to nickel compounds has been considered as one of the potential causes of human lung cancer. However, the molecular mechanism of nickel-induced lung carcinogenesis remains obscure. In the current study, slight S-phase increase, significant G(2)/M cell cycle arrest, and proliferation blockage were observed in human bronchial epithelial cells (Beas-2B) upon nickel exposure. Moreover, the induction of cyclin D1 and cyclin E by nickel was shown for the first time in human pulmonary cells, which may be involved in nickel-triggered G(1)/S transition and cell transformation. In addition, we verified that hypoxia-inducible factor-1alpha, an important transcription factor of nickel response, was not required for the cyclin D1 or cyclin E induction. The role of p53 in nickel-induced G(2)/M arrest was excluded, respecting that its protein level, ser(15) phosphorylation, and transcriptional activity were not changed in nickel response. Further study revealed that cyclin A was not activated in nickel response, and cyclin B1, which not only promotes G(2)/M transition but also prevents M-phase exit of cells if not degraded in time, was up-regulated by nickel through a manner independent of hypoxia-inducible factor. More importantly, our results verified that overexpressed cyclin B1, veiling the effect of cyclin D1 or cyclin E, mediated nickel-caused M-phase blockage and cell growth inhibition, which may render pulmonary cells more sensitive to DNA damage and facilitates cancer initiation. These results will not only deepen our understanding of the molecular mechanism involved in nickel carcinogenecity, but also lead to the further study on chemoprevention of nickel-associated human cancer.

SUBMITTER: Ding J

PROVIDER: S-EPMC3874128 | biostudies-literature | 2009 Jun

REPOSITORIES: biostudies-literature

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Effects of nickel on cyclin expression, cell cycle progression and cell proliferation in human pulmonary cells.

Ding Jin J He Guoping G Gong Wenfeng W Wen Wen W Sun Wen W Ning Beifang B Huang Shanna S Wu Kun K Huang Chuanshu C Wu Mengchao M Xie Weifen W Wang Hongyang H

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20090601 6

Frequent exposure to nickel compounds has been considered as one of the potential causes of human lung cancer. However, the molecular mechanism of nickel-induced lung carcinogenesis remains obscure. In the current study, slight S-phase increase, significant G(2)/M cell cycle arrest, and proliferation blockage were observed in human bronchial epithelial cells (Beas-2B) upon nickel exposure. Moreover, the induction of cyclin D1 and cyclin E by nickel was shown for the first time in human pulmonary ...[more]

PMID: 19505905

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Project description:BackgroundPulmonary hypertension (PH) is a chronic vascular disease characterized, among other abnormalities, by hyperproliferative smooth muscle cells and a perturbed cellular redox and metabolic balance. Oxidants induce cell cycle arrest to halt proliferation; however, little is known about the redox-regulated effector proteins that mediate these processes. Here, we report a novel kinase-inhibitory disulfide bond in cyclin D-CDK4 (cyclin-dependent kinase 4) and investigate its role in cell proliferation and PH.MethodsOxidative modifications of cyclin D-CDK4 were detected in human pulmonary arterial smooth muscle cells and human pulmonary arterial endothelial cells. Site-directed mutagenesis, tandem mass-spectrometry, cell-based experiments, in vitro kinase activity assays, in silico structural modeling, and a novel redox-dead constitutive knock-in mouse were utilized to investigate the nature and definitively establish the importance of CDK4 cysteine modification in pulmonary vascular cell proliferation. Furthermore, the cyclin D-CDK4 oxidation was assessed in vivo in the pulmonary arteries and isolated human pulmonary arterial smooth muscle cells of patients with pulmonary arterial hypertension and in 3 preclinical models of PH.ResultsCyclin D-CDK4 forms a reversible oxidant-induced heterodimeric disulfide dimer between C7/8 and C135, respectively, in cells in vitro and in pulmonary arteries in vivo to inhibit cyclin D-CDK4 kinase activity, decrease Rb (retinoblastoma) protein phosphorylation, and induce cell cycle arrest. Mutation of CDK4 C135 causes a kinase-impaired phenotype, which decreases cell proliferation rate and alleviates disease phenotype in an experimental mouse PH model, suggesting this cysteine is indispensable for cyclin D-CDK4 kinase activity. Pulmonary arteries and human pulmonary arterial smooth muscle cells from patients with pulmonary arterial hypertension display a decreased level of CDK4 disulfide, consistent with CDK4 being hyperactive in human pulmonary arterial hypertension. Furthermore, auranofin treatment, which induces the cyclin D-CDK4 disulfide, attenuates disease severity in experimental PH models by mitigating pulmonary vascular remodeling.ConclusionsA novel disulfide bond in cyclin D-CDK4 acts as a rapid switch to inhibit kinase activity and halt cell proliferation. This oxidative modification forms at a critical cysteine residue, which is unique to CDK4, offering the potential for the design of a selective covalent inhibitor predicted to be beneficial in PH.

Project description:Background:Aberrant proliferation of retinal pigment epithelial (RPE) cells under pathologic condition results in the occurrence of proliferative vitreoretinopathy (PVR). Icariin (ICA)-a flavonol glucoside-has been shown to inhibit proliferation of many cell types, but the effect on RPE cells is unknown. This study aimed to clarify the inhibitory effects of ICA on RPE cells against platelet-derived growth factor (PDGF)-BB-induced cell proliferation, and discuss the regulatory function of H19 in RPE cells. Methods:MTS assay was conducted to determine the effects of ICA on cell proliferation. Flow cytometry analysis was performed to detect cell cycle progression. Quantitative real-time PCR and western blot assay were used to measure the expression patterns of genes in RPE cells. Results:ICA significantly suppressed PDGF-BB-stimulated RPE cell proliferation in a concentration-dependent manner. Moreover, since administration of ICA induced cell cycle G0/G1 phase arrest, the anti-proliferative activity of ICA may be due to G0/G1 phase arrest in RPE cells. At molecular levels, cell cycle regulators cyclin D1, CDK4, CDK6, p21 and p53 were modulated in response to treatment with ICA. Most importantly, H19 was positively regulated by ICA and H19 depletion could reverse the inhibitory effects of ICA on cell cycle progression and proliferation in PDGF-BB-stimulated RPE cells. Further mechanical explorations showed that H19 knockdown resulted in alternative expressions levels of cyclin D1, CDK4, CDK6, p21 and p53 under ICA treatment. Conclusions:Our findings revealed that ICA was an effective inhibitor of PDGF-BB-induced RPE cell proliferation through affecting the expression levels of cell cycle-associated factors, and highlighted the potential application of ICA in PVR therapy. H19 was described as a target regulatory gene of ICA whose disruption may contribute to excessive proliferation of RPE cells, suggesting that modulation of H19 expression may be a novel therapeutic approach to treat PVR.

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Effects of nickel on cyclin expression, cell cycle progression and cell proliferation in human pulmonary cells.

Publications

Effects of nickel on cyclin expression, cell cycle progression and cell proliferation in human pulmonary cells.

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