title: Downregulation of cyclin D1-CDK4 protein in human embryonic lung fibroblasts (HELF) induced by silica is mediated through the ERK and JNK pathway.
abstract: Silica is a factor in the induction of acute injury and chronic pulmonary fibrosis. In 1996, silica was also listed as a human carcinogen by the International Agency for Research on Cancer (IARC). However, the molecular mechanisms involved in its pathologic effects are not well understood. We found that exposure of human embryonic lung fibroblasts (HELF) to crystalline silica for 2h decreased cyclin D1 and cyclin-dependent kinase 4 (CDK4) expression levels. Extracellular signal-regulated protein kinase (ERKs), c-Jun NH2-terminal amino kinase (JNKs), and p38 kinase, as well as their downstream transcription factor, AP-1, had different effects on the regulation of expression levels of cyclin D1 and CDK4 alterations induced by silica. Silica activates multiple signal transduction pathways involved in coordinating cellular responses to stress. We established the requirements for ERK and JNK, members of the mitogen-activated protein kinase (MAPK) family, in mediating G1 phase arrest of HELF induced by silica. Silica treatment activated ERK in a dose-dependent manner. AG126 (a chemical inhibitor of the ERK signaling pathway) and the dominant negative mutant of ERK2 (a molecular inhibitor of ERK2) prevented decreases in cyclin D1 and CDK4 expression levels. A chemical inhibitor of JNK, SP600125, prevented the decreased expression of both cyclin D1 and CDK4, whereas SB203580, a chemical inhibitor of p38, did not. Interestingly, curcumin prevented the decrease in DK4 expression, but not in cyclin D1. These results demonstrate that ERKs and JNKs are responsible for the decrease of cyclin D1 and CDK4 expression levels in HELF induced by silica. Activator protein-1 (AP-1) was responsible for the decrease of CDK4 expression level, but not that of cyclin D1. The findings help to explain the mechanisms of diseases induced by silica.
authors.affiliation: Department of Prevention Medicine, North China Coal Medical University, 57 South Jian She Road, Tangshan 063000, PR China.
authors.forename: Fuhai
authors.initials: F
authors.lastname: Shen
authors.forename: Xueyun
authors.initials: X
authors.lastname: Fan
authors.forename: Bingci
authors.initials: B
authors.lastname: Liu
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Jia
authors.forename: Ai
authors.initials: A
authors.lastname: Gao
authors.forename: Hongju
authors.initials: H
authors.lastname: Du
authors.forename: Meng
authors.initials: M
authors.lastname: Ye
authors.forename: Baorong
authors.initials: B
authors.lastname: You
authors.forename: Chuanshu
authors.initials: C
authors.lastname: Huang
authors.forename: Xianglin
authors.initials: X
authors.lastname: Shi
mesh_terms: D002478:Cells, Cultured; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D004622:Embryo, Mammalian / Q000033:anatomy & histology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000196:embryology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D012822:Silicon Dioxide / Q000494:pharmacology*; D012829:Silicosis / Q000378:metabolism / Q000473:pathology; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; 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