title: Up-regulation of cyclin D1 by JNK1/c-Jun is involved in tumorigenesis of human embryo lung fibroblast cells induced by a low concentration of arsenite.
abstract: Inorganic arsenic, a ubiquitous environmental contaminant, is associated with an increased risk of cancer. There are several hypotheses regarding arsenic-induced carcinogenesis. The mechanism of action remains obscure, although hyper-proliferation of cells is involved. In the present study, the molecular mechanisms underlying the proliferation and malignant transformation of human embryo lung fibroblast (HELF) cells induced by a low concentration of arsenite were investigated. The results reveal that a low concentration of arsenite induces cell proliferation and promotes cell cycle transition from the G(1) to the S phase. Moreover, arsenite activates the JNK1/c-Jun signal pathway, but not JNK2, which up-regulates the expression of cyclin D1/CDK4 and phosphorylates the retinoblastoma (Rb) protein. Blocking of the JNK1/c-Jun signal pathway suppresses the increases of cyclin D1 expression and Rb phosphorylation, which attenuates cell proliferation, reduces the transition from the G1 to the S phase, and thereby inhibits the neoplastic transformation of HELF cells induced by a low concentration of arsenite. Thus, activation of the JNK1/c-Jun pathway up-regulates the expression of cyclin D1, which is involved in the tumorigenesis caused by a low concentration of arsenite.
authors: Department of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, PR China.
authors: Yuan
authors: Y
authors: Li
authors: Lu
authors: L
authors: Shen
authors: Hui
authors: H
authors: Xu
authors: Ying
authors: Y
authors: Pang
authors: Yuan
authors: Y
authors: Xu
authors: Min
authors: M
authors: Ling
authors: Jianwei
authors: J
authors: Zhou
authors: Xinru
authors: X
authors: Wang
authors: Qizhan
authors: Q
authors: Liu
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology / Q000627:therapeutic use; D018053:Arsenites / Q000008:administration & dosage / Q000633:toxicity*; D002274:Carcinogens, Environmental / Q000008:administration & dosage / Q000633:toxicity; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced* / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019938:Cyclin D1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000637:transplantation; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008819:Mice, Nude; D048055:Mitogen-Activated Protein Kinase 8 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D016755:Proto-Oncogene Proteins c-jun / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000187:drug effects; D017670:Sodium Compounds / Q000008:administration & dosage / Q000633:toxicity*; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D016588:Anticarcinogenic Agents; D018053:Arsenites; C530104:CCND1 protein, human; D002274:Carcinogens, Environmental; D047428:Protein Kinase Inhibitors; D016755:Proto-Oncogene Proteins c-jun; D034741:RNA, Small Interfering; D017670:Sodium Compounds; D019938:Cyclin D1; C017947:sodium arsenite; D048055:Mitogen-Activated Protein Kinase 8