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

Fuhai Shen, Xueyun Fan, Bingci Liu, Xiaowei Jia, Hongju Du, Baorong You, Meng Ye, Chuanshu Huang, Xianglin Shi

Research output: Contribution to journalArticlepeer-review

27 Scopus citations


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.

Original languageEnglish
Pages (from-to)185-195
Number of pages11
JournalToxicology Letters
Issue number3
StatePublished - Jan 25 2006

Bibliographical note

Funding Information:
This work was supported by grants of National Natural Science Foundation of China (30371206 and 30440420593) and 973 National Key Basic Research and Development Program (2002 CB 512905).


  • AP-1
  • CDK4
  • Carcinogenesis
  • Cyclin D1
  • MAPK
  • Silica

ASJC Scopus subject areas

  • Toxicology


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