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Vol. 16, Issue 12, 5579-5591, December 2005

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Transcriptional Regulation of Cyclooxygenase-2 in Response to Proteasome Inhibitors Involves Reactive Oxygen Species-mediated Signaling Pathway and Recruitment of CCAAT/Enhancer-binding Protein and CREB-binding Protein

Department of Pharmacology, College of Medicine, National Taiwan University, Taipei 10018, Taiwan

Submitted August 18, 2005; Accepted September 21, 2005
Monitoring Editor: J. Silvio Gutkind

Inhibition of ubiquitin-proteasome pathway has been shown to be a promising strategy for the treatment of inflammation and cancer. Here, we show that proteasome inhibitors MG132, PSI-1, and lactacystin induce COX-2 expression via enhancing gene transcription rather than preventing protein degradation in the human alveolar NCI-H292 and A549, and gastric AGS epithelial cells. NF-IL6 and CRE, but not NF-B elements on the COX-2 promoter were involved in the gene transcription event. The binding of CCAAT/enhancer binding protein (C/EBP) and C/EBP to the CRE and NF-IL6 elements, as well as the recruitment of CBP and the enhancement of histone H3 and H4 acetylation on the COX-2 promoter was enhanced by MG132. However, it did not affect the total protein levels of C/EBP and C/EBP. MG132-induced DNA-binding activity of C/EBP, but not C/EBP was regulated by p38, PI3K, Src, and protein kinase C. Small interfering RNA of C/EBP suppressed COX-2 expression, further strengthening the role of C/EBP in COX-2 gene transcription. In addition, the generation of intracellular reactive oxygen species (ROS) in response to MG132 contributed to the activation of MAPKs and Akt. These findings reveal that the induction of COX-2 transcription induced by proteasome inhibitors requires ROS-dependent protein kinases activation and the subsequent recruitments of C/EBP and CBP.

Abbreviations used: NF-B, nuclear factor B; NF-IL6, nuclear factor for interleukin 6; IL, interleukin; PI3K, phosphatidylinositol 3-kinase; RT-PCR, reverse transcription-polymerase chain reaction; TNF, tumor necrosis factor.

^* These authors contributed equally to this work.

Address correspondence to: Ching-Chow Chen (ccchen{at}ha.mc.ntu.edu.tw).

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