JNK-ATF-2 inhibits thrombomodulin (TM) expression by recruiting histone deacetylase4 (HDAC4) and forming a transcriptional repression complex in the TM promoter

Edited by Veli-Pekka Lehto

Received 24 November 2009; received in revised form 18 January 2010; accepted 21 January 2010. published online 29 January 2010.

Abstract

Thrombomodulin (TM) is an important vascular protective molecule that has anticoagulant, anti-inflammatory and anti-apoptotic properties. TM is downregulated in many thrombotic and vascular diseases. However, the mechanisms responsible for TM suppression are not completely understood. In this study, we investigated the mechanism involved in fatty acid-induced suppression of TM expression in human aortic endothelial cells. We found that palmitic acid inhibited TM expression through the JNK and p38 pathways. ATF-2, a JNK and p38 target transcription factor, was involved in the suppression. ATF-2 can bind to the TM promoter, recruit HDAC4 and form a transcriptional repression complex in the promoter, which may lead to chromatin condensation and transcriptional arrest. This study provides novel insight into TM down-regulation by stress signaling pathways.

Structured summary

MINT-7555703, MINT-7555712: HDAC4 (uniprotkb:P56524) physically interacts (MI:0915) with ATF-2 (uniprotkb:P15336) by anti bait coimmunoprecipitation (MI:0006)

Keywords: Palmitic acid (hexadecanoic acid), Thrombomodulin, JNK, p38, ATF-2, Histone deacetylase4 (HDAC4)

a The key laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital, Shandong University, Jinan, Shandong, China

b Division of Cardiothoracic Surgery, The Department of Surgery, Baylor College of Medicine, Houston, TX, USA

c Texas Heart Institute, Houston, TX, USA

Corresponding authors. Address: Division of Cardiothoracic Surgery, The Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA.

1 These authors contributed equally.

PII: S0014-5793(10)00081-5

doi:10.1016/j.febslet.2010.01.048

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