RT Journal Article
SR Electronic
T1 Activation of Extracellular Signal-Regulated Kinase Signaling by Epidermal Growth Factor Mediates c-Jun Activation and p300 Recruitment in Keratin 16 Gene Expression
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 85
OP 98
DO 10.1124/mol.105.016220
VO 69
IS 1
A1 Ying-Nai Wang
A1 Yun-Ju Chen
A1 Wen-Chang Chang
YR 2006
UL http://molpharm.aspetjournals.org/content/69/1/85.abstract
AB In studies of gene regulation of keratin 16, we reported previously that simian virus 40 promoter factor 1 shows a functional cooperation with c-Jun and coactivators p300/CBP in driving the transcriptional regulation of epidermal growth factor (EGF)-induced keratin 16 gene expression. In the present study, we found that the stimulated expression of keratin 16 by EGF was mediated mainly through the mitogen-activated protein kinase kinase–extracellular signal-regulated kinases 1 and 2 (ERK1/2) signaling pathway. Ser63 and Ser73 on the c-Jun NH2-terminal transactivation domain could be phosphorylated in cells treated with EGF; nevertheless, we found that the c-Jun COOH terminus played a pivotal role in EGF-induced expression of keratin 16. The activation of keratin 16 by EGF treatment could not gbe enhanced by the overexpression of myc-c-JunK3R, in which three putative acetylation lysine residues on the c-Jun COOH terminus were all mutated into arginines, suggesting that c-Jun acetylation on the COOH terminus might partially play a functional role in this system. In addition, by using a chromatin immunoprecipitation assay and a DNA affinity precipitation assay, EGF treatment up-regulated the p300 recruitment through ERK signaling to the promoter region in regulating keratin 16 transcriptional activity. Furthermore, the enhancement of acetyl-histone H3 to the keratin 16 chromatin promoter induced by EGF was also mediated via ERK activation. In conclusion, these results strongly suggest that both c-Jun induction and p300 recruitment to gene promoter, mediated through ERK activation, played an essential role in regulating keratin 16 gene expression by EGF. p300 mediated and regulated EGF-induced keratin 16 gene expression, at least in part, through multiple mechanisms, including a selective acetylation of c-Jun and histone H3.