PMID:18234971
| Citation |
Zhang, D, Li, J, Song, L, Ouyang, W, Gao, J and Huang, C (2008) A JNK1/AP-1-dependent, COX-2 induction is implicated in 12-O-tetradecanoylphorbol-13-acetate-induced cell transformation through regulating cell cycle progression. Mol. Cancer Res. 6:165-74 |
|---|---|
| Abstract |
Cyclooxygenase-2 (COX-2) is reported to be one of the early-response gene products induced by 12-O-tetradecanoylphorbol-13-acetate (TPA). However, the relevance of COX-2 in TPA-induced cell transformation and the underlying mechanisms remains to be explored. Initially, we verified COX-2 induction after TPA treatment in mouse embryonic fibroblasts (MEF) and mouse epidermal cells Cl 41. More importantly, introduction of COX-2 small interfering RNA in MEFs or Cl 41 cells suppressed the cell transformation caused by TPA treatment. This inhibition could be reversed by overexpression of human full-length COX-2, indicating that COX-2 is at least one of the critical molecules involved in TPA-induced cell transformation. We further showed that TPA-promoted cell cycle progression was partially suppressed by COX-2 small interfering RNA, indicating that COX-2 also participated in TPA-associated cell cycle progression. Investigation of the upstream signaling pathways revealed that c-Jun-NH(2)-kinase 1 (JNK1), but not JNK2, played important roles in COX-2 induction, because knockout of JNK1 gene rather than JNK2 gene markedly impaired COX-2 induction. Furthermore, inhibition of c-Jun/activator protein 1 pathway or JNKs/c-Jun pathway by overexpression of dominant negative mutants of c-Jun, or MKK4 and MKK7 together, resulted in impairment of COX-2 induction, suggesting that JNK1/c-Jun/activator protein 1 pathway is involved in TPA-associated COX-2 induction. In contrast, IKK/p65 nuclear factor-kappaB pathway was not implicated because knockout of IKKalpha, IKKbeta, or p65 gene did not affect COX-2 induction although nuclear factor-kappaB was activated by TPA. In addition, the TPA-promoted cell cycle progression was found impaired in JNK1-deficient, but not in JNK2-deficient, MEFs. Our results show that JNK1-associated COX-2 induction is implicated in TPA-associated cell transformation and cell cycle progression. |
| Links |
PubMed Online version:10.1158/1541-7786.MCR-07-0181 |
| Keywords |
Animals; Cell Cycle/drug effects; Cell Transformation, Neoplastic/drug effects; Cyclooxygenase 2/biosynthesis; Enzyme Induction/drug effects; Fibroblasts/cytology; Fibroblasts/drug effects; Fibroblasts/enzymology; Humans; I-kappa B Kinase/metabolism; Mice; Mitogen-Activated Protein Kinase 8/metabolism; Mitogen-Activated Protein Kinase 9/metabolism; Tetradecanoylphorbol Acetate/pharmacology; Transcription Factor AP-1/metabolism; Transcription Factor RelA/metabolism |
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