This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 26/6/1323    most recent 01.ATV.0000220383.19192.55v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Singh, N. N. Articles by Ramji, D. P. Search for Related Content PubMed PubMed Citation Articles by Singh, N. N. Articles by Ramji, D. P. Related Collections Cell signalling/signal transduction Gene expression Gene regulation Growth factors/cytokines

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:1323.)
© 2006 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Transforming Growth Factor-ß–Induced Expression of the Apolipoprotein E Gene Requires c-Jun N-Terminal Kinase, p38 Kinase, and Casein Kinase 2

Nishi N. Singh; Dipak P. Ramji

From the Cardiff School of Biosciences, Cardiff University, United Kingdom.

Correspondence to Dipak P. Ramji, Cardiff School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3US, UK. E-mail Ramji{at}cardiff.ac.uk

Objective— The cytokine transforming growth factor-ß (TGF-ß) and apolipoprotein E (apoE) play potent antiatherogenic roles. Despite such importance, the mechanisms underlying the regulation of apoE expression by TGF-ß have not been characterized and were therefore investigated.

Methods and Results— Using THP-1 cell line as a model system, with key findings confirmed in primary cultures, we show that TGF-ß induces the expression of apoE, and this is prevented by pharmacological inhibitors of c-Jun N-terminal kinase (JNK), p38 kinase, and casein kinase 2 (CK2). In support for an important role for these pathways, TGF-ß activates JNK, p38 kinase, and CK2, and dominant-negative (DN) forms of these proteins inhibit the cytokine-induced apoE expression. TGF-ß also increases the phosphorylation and expression of c-Jun, a downstream target for JNK action and a component of activator protein-1 (AP-1), and DN c-Jun inhibits the induction of apoE expression in response to the cytokine. AP-1 DNA binding was also induced by TGF-ß, and the action of p38 kinase, JNK, and CK2 converged on the activation of c-Jun/AP-1.

Conclusions— These studies reveal a novel role for JNK, p38 kinase, CK2, and c-Jun/AP-1 in the TGF-ß–induced expression of apoE.

The mechanisms underlying the regulation of apolipoprotein E expression in monocytes/macrophages by the antiatherogenic cytokine TGF-ß were investigated. We show a novel role for JNK, p38 kinase, CK2, and c-Jun/AP-1 in the response, which have implications to the development of atherosclerosis.

Key Words: apolipoprotein E • atherosclerosis • macrophage • TGF-ß • signal transduction • gene expression

This article has been cited by other articles:

				M. Kockx, W. Jessup, and L. Kritharides Regulation of Endogenous Apolipoprotein E Secretion by Macrophages Arterioscler Thromb Vasc Biol, June 1, 2008; 28(6): 1060 - 1067. [Abstract] [Full Text] [PDF]

				P. Antonson, T. Jakobsson, T. Almlof, K. Guldevall, K. R. Steffensen, and J.-A. Gustafsson RAP250 Is a Coactivator in the Transforming Growth Factor {beta} Signaling Pathway That Interacts with Smad2 and Smad3 J. Biol. Chem., April 4, 2008; 283(14): 8995 - 9001. [Abstract] [Full Text] [PDF]

				K. Drosatos, D. Sanoudou, K. E. Kypreos, D. Kardassis, and V. I. Zannis A Dominant Negative Form of the Transcription Factor c-Jun Affects Genes That Have Opposing Effects on Lipid Homeostasis in Mice J. Biol. Chem., July 6, 2007; 282(27): 19556 - 19564. [Abstract] [Full Text] [PDF]

				E. J. Harvey, N. Li, and D. P. Ramji Critical Role for Casein Kinase 2 and Phosphoinositide-3-Kinase in the Interferon-{gamma}-Induced Expression of Monocyte Chemoattractant Protein-1 and Other Key Genes Implicated in Atherosclerosis Arterioscler Thromb Vasc Biol, April 1, 2007; 27(4): 806 - 812. [Abstract] [Full Text] [PDF]