Downregulation of cyclin D1-CDK4 protein in human embryonic lung fibroblasts (HELF) induced by silica is mediated through the ERK and JNK pathway

Authors

  • Fuhai Shen,

    1. Department of Prevention Medicine, North China Coal Medical University, 57 South Jian She Road, Tangshan 063000, PR China
    Search for more papers by this author
  • Xueyun Fan,

    1. Department of Prevention Medicine, North China Coal Medical University, 57 South Jian She Road, Tangshan 063000, PR China
    Search for more papers by this author
  • Bingci Liu,

    Corresponding author
    1. National Institute of Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, 29 Nan Wei Road, Beijing 100050, PR China
    Search for more papers by this author
  • Xiaowei Jia,

    1. National Institute of Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, 29 Nan Wei Road, Beijing 100050, PR China
    Search for more papers by this author
  • Ai Gao,

    1. National Institute of Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, 29 Nan Wei Road, Beijing 100050, PR China
    Search for more papers by this author
  • Hongju Du,

    1. National Institute of Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, 29 Nan Wei Road, Beijing 100050, PR China
    Search for more papers by this author
  • Meng Ye,

    1. National Institute of Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, 29 Nan Wei Road, Beijing 100050, PR China
    Search for more papers by this author
  • Baorong You,

    1. National Institute of Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, 29 Nan Wei Road, Beijing 100050, PR China
    Search for more papers by this author
  • Chuanshu Huang,

    1. Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, USA
    Search for more papers by this author
  • Xianglin Shi

    1. Shanghai Institute for Nutrition Sciences, Chinese Academy of Sciences, 294 Tai Yuan Road, Shanghai 200031, PR China
    Search for more papers by this author

Corresponding author. Tel.\fax: +86 10 83132527. bcliu@263.net

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 2 h 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.

Ancillary