title: Roles of the ERK, JNK/AP-1/cyclin D1-CDK4 pathway in silica-induced cell cycle changes in human embryo lung fibroblast cells.
abstract: Silica is a potent occupational fibrogenic agent capable of inducing lung fibrosis and many other lung diseases. Our current study focused on the signalling pathways regulating cell cycle changes in HELF (human embryo lung fibroblast) after silica (α-quartz) exposure. Our results showed silica exposure could lead to cell cycle changes. The cell cycle alternations were accompanied with overexpression of cyclin D1 and CDK4 (cyclin-dependent kinase 4) in a time-dependent manner. Silica exposure also decreased E2F-4 expression in HELF. These changes were blocked by overexpression of dominant-negative mutants of ERK (extracellular signal-regulated protein kinase) or the JNK (stress-activated c-Jun NH2-terminal kinase), respectively. Moreover, pretreatment of cells with curcumin, an activation of AP-1 (activator protein-1) inhibitor, inhibited silica-induced cell cycle alteration, the decreased expression of E2F-4 and overexpression of cyclin D1 and CDK4. Furthermore, both antisense cyclin D1 and antisense CDK4 can block silica-induced cell cycle changes. These results suggest that silica exposure can induce cell cycle changes, which may be mediated through ERK, JNK/AP-1/cyclin D1-CDK4-dependent pathway.
authors.affiliation: National Institute of Occupation Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing, Peoples Republic of China.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Jia
authors.forename: Bingci
authors.initials: B
authors.lastname: Liu
authors.forename: Xianglin
authors.initials: X
authors.lastname: Shi
authors.forename: Meng
authors.initials: M
authors.lastname: Ye
authors.forename: Fengmei
authors.initials: F
authors.lastname: Zhang
authors.forename: Haifeng
authors.initials: H
authors.lastname: Liu
mesh_terms: D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D003474:Curcumin / Q000494:pharmacology; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics / Q000378:metabolism*; D050704:E2F4 Transcription Factor / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D015870:Gene Expression / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000166:cytology / Q000378:metabolism; D010957:Plasmids; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D012822:Silicon Dioxide / Q000009:adverse effects*; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: D050704:E2F4 Transcription Factor; D034741:RNA, Small Interfering; D018808:Transcription Factor AP-1; D019938:Cyclin D1; D012822:Silicon Dioxide; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D003474:Curcumin