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Vol. 18, Issue 3, 1118-1127, March 2007

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PP2B-mediated Dephosphorylation of c-Jun C Terminus Regulates Phorbol Ester-induced c-Jun/Sp1 Interaction in A431 Cells

Ben-Kuen Chen^*,, Chi-Chen Huang^*,, Wei-Chiao Chang^*, Yun-Ju Chen^*, Ushio Kikkawa, Ken-ichi Nakahama, Ikuo Morita, and Wen-Chang Chang^*

*Department of Pharmacology, College of Medicine, and Center for Gene Regulation and Signal Transduction Research, National Cheng Kung University, Tainan 701, Taiwan; Biosignal Research Center, Kobe University, Kobe 657-8501, Japan; and Department of Cellular Physiological Chemistry, Tokyo Medical and Dental University, 113-8549 Tokyo, Japan

Submitted September 8, 2006; Revised December 7, 2006; Accepted January 2, 2007
Monitoring Editor: Carl-Henrik Heldin

The c-Jun/Sp1 interaction is essential for growth factor- and phorbol 12-myristate 13-acetate (PMA)-induced genes expression, including human 12(S)-lipoxygenase, keratin 16, cytosolic phospholipase A2, p21^WAF1/CIP1, and neuronal nicotinic acetylcholine receptor 4. Here, we examined the mechanism underlying the PMA-induced regulation on the interaction between c-Jun and Sp1. We found that treatment of cells with PMA induced a dephosphorylation at the C terminus of c-Jun at Ser-243 and a concomitant inhibition of PP2B by using PP2B small interfering RNA, resulting in reduction of PMA-induced gene expression as well as the c-Jun/Sp1 interaction. The c-Jun mutant TAM-67-3A, which contains three substitute alanines at Thr-231, Ser-243, and Ser-249 compared with TAM-67, binds more efficaciously with Sp1 and is about twice as efficacious as TAM-67 in inhibiting the PMA-induced activation of the 12(S)-lipoxygenase promoter. Importantly, PP2B not only dephosphorylates the c-Jun at Ser-243 but also interacts with c-Jun in PMA-treated cells. PMA stimulates the association of the PP2B/c-Jun/Sp1 complex with the promoter. These findings indicate the dephosphorylation of c-Jun C terminus is required for the c-Jun/Sp1 interaction and reveal that PP2B plays an important role in regulating c-Jun/Sp1 interaction in PMA-induced gene expression.

These authors contributed equally to this work.

Address correspondence to: Wen-Chang Chang (wcchang{at}mail.ncku.edu.tw)

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