Overexpression of cyclin D1-CDK4 in silica-induced transformed cells is due to activation of ERKs, JNKs/AP-1 pathway

Toxicol Lett. 2006 Jan 25;160(3):185-95. doi: 10.1016/j.toxlet.2005.07.009. Epub 2005 Aug 25.


Silica has been known to be a factor inducing acute injury and chronic pulmonary fibrosis. Silica has also been listed as a human carcinogen in 1996 by International Agency for Research on Cancer (IARC). However, the molecular mechanisms involved its pathologic effects are not well understood. In these studies, we found that exposure of human embryonic lung fibroblasts (HELF) to crystalline silica could cause increases in activation of extracellular signal-regulated kinases (ERKs), p38K, and c-Jun NH2-terminal amino kinases (JNKs), and HELF transformation. Interestingly, silica-induced transformation of HELF (S-HELF) led to increases in activated levels of ERKs and p46 of JNKs, and decrease in p38K activation, and no effect on activation of p54 of JNKs, as compared with those in parental HELF. Further studies showed that there are differential effects of ERKs, JNKs and p38K, as well as their downstream transcription factor AP-1, in regulation of expression of cyclin D1 and CDK4 and cell cycle alternations induced by silica. Cyclin D1 and CDK4 were increased in S-HELF as compared with those in HELF. Inhibition of ERKs activation by AG126, JNK by SP600125, and AP-1 by curcumin could reduced the induction of cyclin D1 and CDK4. There is no significant difference for cell cycle distribution between groups. These results demonstrate that ERKs and JNKs, but not p38K is responsible for induction of cyclin D1 and CDK4 in S-HELF, suggesting that overexpression of cyclin D1 and CDK4 caused by silica is mediated by ERK, JNK/AP-1signaling pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blotting, Western
  • Cell Line, Transformed
  • Cell Proliferation / drug effects
  • Cyclin D1 / biosynthesis*
  • Cyclin-Dependent Kinase 4 / biosynthesis*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Fibroblasts / drug effects*
  • Fibroblasts / enzymology
  • Fibroblasts / metabolism
  • Flow Cytometry
  • Humans
  • Immunohistochemistry
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Mitogen-Activated Protein Kinases / metabolism*
  • Signal Transduction / drug effects
  • Silicon Dioxide / toxicity*
  • Transcription Factor AP-1 / metabolism*
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Transcription Factor AP-1
  • Cyclin D1
  • Silicon Dioxide
  • CDK4 protein, human
  • Cyclin-Dependent Kinase 4
  • Extracellular Signal-Regulated MAP Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases