Volume 11 Issue 10 - December 18, 2009 PDF
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Sumoylation of LAP1 is involved in the HDAC4-mediated repression of COX-2 transcription
Wen-Ling Wang1, Yi-Chao Lee2,4, Wen-Ming Yang5, Wen-Chang Chang1-4,* and Ju-Ming Wang3,4

1Institute of Basic Medical Sciences and 2Department of Pharmacology, College of Medicine, 3Institute of Biosignal Transduction, College of Bioscience and Biotechnology, 4Center for Gene Regulation and Signal Transduction Research, National Cheng Kung University, Tainan, and 5Institute of Molecular Biology, Chung Hsing University, Taichung, Taiwan.
wcchang@mail.ncku.edu.tw

Nuc. Acids Res. 2008, 36 (19): 6066-6079.

 
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Dr. Wen-Chang Chang
Gene transcription is the fundamental of life science. It not only provides the explanations of cellular phenomena but also serves as the target for linking basis medical science and clinical medicine. Our laboratory recently is interested in investigating the molecular mechanisms of activation and repression of transcription of inflammation-related genes.

COX-2 is an inducible enzyme that is induced by cytokines, growth factors, endotoxins and oncogenes in different cell types. The CCAAT/enhancer binding proteins (C/EBPs) are involved in the regulation of COX-2 transcription. Six C/EBP members have been identified in mammalian cells. Among them, CEBPA, CEBPB and CEBPD have been mentioned to regulate COX-2 transcription in many reports. However, how the C/EBPs members coordinate with chromatin remodeling enzymes and how they interplay with coactivators and corepressors to involve in the transcriptional regulation of COX-2 gene remain unclear.

Our previous reports published in 2006 Nucl. Acids Res. demonstrated that CEBPD mediates in the EGF-induced COX-2 transcription, suggesting that CEBPD acts as a bifunctional transcription factor on COX-2 gene suppression and activation by post-translational modification (1). Briefly, the sumoylated CEBPD (suCEBPD) has the ability to recruit corepressors to regulate gene expression. Moreover, the sumoylation of CEBPD has no effect on its DNA binding activity. Therefore, the transient increase of CEBPD can replace the suCEBPD to serve as an activator to mediate the bindings of coactivators on the promoters of downstream targets and further stimulate their transiently transcriptional activation. Although many genes were reported to be activated in a transient manner, but seldom of them were characterized for the molecular mechanism of transcriptional regulation. Following our previous study, we found that the COX-2 transcription upon EGF treatment is in transient activation. Therefore, we are interested to characterize how the two C/EBPs family members interplay in the EGF-induced COX-2 transcription. Meanwhile, we would also like to reveal the re-inactivation of the COX-2 gene expression upon long-term EGF treatment. In our recent publication of 2008 Nucl. Acids Res., we found that the long-term EGF treatment can induce LAP1 activation, an isoform of another C/EBPs family members-CEBPBs. The increase of LAP1 is coincident with COX-2 mRNA decreasing. Therefore, we speculated that the LAP1 plays a functional role in the reinactivation of COX-2 transcription. In addition, the sumoylation of LAP1 is increased during the lagging stage of EGF treatment. We further suspected whether the sumoylation of LAP1 participate in the repression of COX-2 transcription. Moreover, we found that long-term EGF treatment can increase the import of HDAC4 in the nucleus. Based on above observations, we designed a series of experiments to link these observations. Using an in vivo DNA binding assay, Chromatin IP, we demonstrated that increase of SUMO1-conjuagted CEBPD and LAP1 is coincident with the HDAC4 binding on the COX-2 promoter in the status of COX-2 gene inactivation. Taken together, we suggested a model for the molecular mechanism of transient activation of COX-2 gene upon EGF treatment. Briefly, in the resting stage or starvation, suCEBPD and suLAP1 could bind to the CRE and CEBP motifs of COX-2 promoter and interact with nuclear HDAC4 to form a repressive complex. In the early 1-4 h of EGF treatment, the immediately induced non-sumoylation of CEBPD and c-Jun can be positive regulators to replace the suCEBPD and suLAP1. This replacement will increase the p300 binding and form an intact initiation of activation complex to stimulate COX-2 transcription. After 4 h of EGF treatment, combination of decreasing binding of c-Jun, non-sumoylated CEBPD and p300, with the increasing binding of suLAP1, suCEBPD and re-import of HDAC4 will re-inactivate COX-2 transcription through the newly formed HDAC4/suCEBPD/suLAP1 complex.
Figure 1. The involvement of CEBPD and LAP1 in the EGF-regulated COX-2 transcription.

References:
  1. Wang WL, Lee YC, Yang WM, Chang WC, Wang JM. Sumoylation of LAP1 is involved in the HDAC4-mediated repression of COX-2 transcription. Nuc. Acids Res. 2008, 36 (19): 6066-6079.
  2. Wang JM, Ko CY, Chen LC, Wang WL, Chang WC. Functional role of NF-IL6 beta and its sumoylation and acetylation modifications in promoter activation of cyclooxygenase 2 gene. Nuc. Acids Res. 2006, 34(1):217-231.
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