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J. Biol. Chem., Vol. 282, Issue 37, 27215-27228, September 14, 2007

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ERK2-mediated C-terminal Serine Phosphorylation of p300 Is Vital to the Regulation of Epidermal Growth Factor-induced Keratin 16 Gene Expression^*

Yun-Ju Chen, Ying-Nai Wang^¶, and Wen-Chang Chang^||1

From the Department of Pharmacology, Institute of Basic Medical Sciences, College of Medicine, ^||Center for Gene Regulation and Signal Transduction Research, National Cheng Kung University, Tainan 701, Taiwan and the ^¶Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030

We previously reported that the epidermal growth factor (EGF) regulates the gene expression of keratin 16 by activating the extracellular signal-regulated kinase 1 and 2 (ERK1/2) signaling which in turn enhances the recruitment of p300 to the keratin 16 promoter. The recruited p300 functionally cooperates with Sp1 and c-Jun to regulate the gene expression of keratin 16. This study investigated in detail the molecular events incurred upon p300 whereby EGF caused an enhanced interaction between p300 and Sp1. EGF apparently induced time- and dose-dependent phosphorylation of p300, both in vitro and in vivo, through the activation of ERK2. The six potential ERK2 phosphorylation sites, including three threonine and three serine residues as revealed by sequential analysis, were first identified in vitro. Confirmation of these six sites in vivo indicated that these three serine residues (Ser-2279, Ser-2315, and Ser-2366) on the C terminus of p300 were the major signaling targets of EGF. Furthermore, the C-terminal serine phosphorylation of p300 stimulated its histone acetyltransferase activity and enhanced its interaction with Sp1. These serine phosphorylation sites on p300 controlled the p300 recruitment to the keratin 16 promoter. When all three serine residues on p300 were replaced by alanine, EGF could no longer induce the gene expression of keratin 16. Taken together, these results strongly suggested that the ERK2-mediated C-terminal serine phosphorylation of p300 was a key event in the regulation of EGF-induced keratin 16 expression. These results also constituted the first report identifying the unique p300 phosphorylation sites induced by ERK2 in vivo.

Received for publication, January 10, 2007 , and in revised form, July 3, 2007.

^* This work was supported in part by Grant NSC 95-2320-B-006-025 from the National Science Council of Republic of China and by the National Cheng Kung University Program for Promoting Academic Excellence and Developing World Class Research Centers. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S4.

¹ To whom correspondence should be addressed. Tel.: 886-6-235-3535, ext. 5496; Fax: 886-6-274-9296; E-mail: wcchang{at}mail.ncku.edu.tw.

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