Nucleic Acids Research Advance Access originally published online on September 27, 2008
Nucleic Acids Research 2008 36(19):6066-6079; doi:10.1093/nar/gkn607
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Nucleic Acids Research, 2008, Vol. 36, No. 19 6066-6079
© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Gene Regulation, Chromatin and Epigenetics |
Sumoylation of LAP1 is involved in the HDAC4-mediated repression of COX-2 transcription
1Institute of Basic Medical Sciences, 2Department of Pharmacology, College of Medicine, 3Center for Gene Regulation and Signal Transduction Research, National Cheng Kung University, Tainan, 4Institute of Molecular Biology, National Chung Hsing University, Taichung and 5Institute of Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan
*To whom correspondence should be addressed. Tel: +886 6 2757575 31067; Fax: +886 6 2083663; Email: yumingw{at}mail.ncku.edu.tw
Correspondence may also be addressed to Wen-Chang Chang. Tel: +886 6 2353535 5496; Fax: +886 6 2749296; Email: wcchang{at}mail.ncku.edu.tw
Received March 1, 2008. Revised September 4, 2008. Accepted September 8, 2008.
CEBPB, one of the CEBP family members, is a crucial regulator of gene expression during innate immunity, inflammatory responses and adipogenesis. In this study, the EGF-induced increase of CEBPB mRNA is shown to be coincident with the decrease of COX-2 mRNA. We identified that all of the individual CEBPB isoforms, LAP1, LAP2 and LIP, attenuate EGF-induced COX-2 promoter activity. Although increased sumoylation of both LAP1 and LAP2 is observed during the lagging stage of EGF treatment, only the sumoylated LAP1, but not the sumoylated LAP2, is responsible for COX-2 gene repression. In addition, EGF treatment can regulate the nucleocytoplasmic redistribution of HDAC4 and SUMO1. We further demonstrated by loss-of- and gain-of-function approaches that HDAC4 can be a negative regulator while inactivating COX-2 transcription. The sumoylation mutant LAP1, LAP1K174A, exhibits an attenuated ability to interact with HDAC4, and increased COX-2 promoter activity. Furthermore, the in vivo DNA binding assay demonstrated that LAP1K174A and CEBPDK120A, sumoylation-defective CEBPD mutants, attenuate the binding of HDAC4 on the COX-2 promoter. In light of the above, our data suggest that the suCEBPD and suLAP1 are involved in the repression of COX-2 transcription through the recruitment of HDAC4.
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