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Papers In Press, published online ahead of print March 1, 2009
J. Lipid Res., doi:10.1194/jlr.M800316-JLR200

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Journal of Lipid Research, Vol. 50, 386-397, March 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

Protein kinase C activation stabilizes LDL receptor mRNA via the JNK pathway in HepG2 cells^*,

Noelle B. Vargas^*, Brandy Y. Brewer^*, Terry B. Rogers^* and Gerald M. Wilson^1,*,

^* Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201
Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201

^* This work was supported by National Institutes of Health grants R01 CA102428 (to G.M.W.) and P01 HL070709 (to T.B.R.) and a Scientist Development Grant from the American Heart Association (to G.M.W.). N.B.V received support from National Institutes of Health grant F31 HL087731, an NIGMS Initiative for Minority Student Development Grant (R25-GM55036), and Procter and Gamble.

The online version of this article (available at http://www.jlr.org) contains supplementary material in the form of one figure and two tables.

Published, JLR Papers in Press, October 20, 2008.

¹ To whom correspondence should be addressed. e-mail: gwils001{at}umaryland.edu

LDL is the most abundant cholesterol transport vehicle in plasma and a major prognostic indicator of atherosclerosis. Hepatic LDL receptors limit circulating LDL levels, since cholesterol internalized by the liver can be excreted. As such, mechanisms regulating LDL receptor expression in liver cells are appealing targets for cholesterol-lowering therapeutic strategies. Activation of HepG2 cells with phorbol esters enhances LDL receptor mRNA levels through transcriptional and posttranscriptional mechanisms. Here, we show that 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced stabilization of receptor mRNA requires the activity of protein kinase C and is accompanied by activation of the major mitogen activated protein kinase pathways. Inhibitor studies demonstrated that receptor mRNA stabilization is independent of the extracellular signal-regulated kinase or p38^MAPK, but requires activation of the c-Jun N-terminal kinase (JNK). An essential role for JNK in stabilizing receptor mRNA was further confirmed through small interfering RNA (siRNA) experiments and by activating JNK through two protein kinase C-independent mechanisms. Finally, prolonged JNK activation increased steady-state levels of receptor mRNA and protein, and significantly enhanced cellular LDL-binding activity. These data suggest that JNK may play an important role in posttranscriptional control of LDL receptor expression, thus constituting a novel mechanism to enhance plasma LDL clearance by liver cells.

Supplementary key words signal transduction • mitogen-activated protein kinase • lipoprotein metabolism • mRNA turnover • gene expression

Abbreviations: actD, actinomycin D; ARE, AU-rich element; BIM, bis-indolylmaleimide I; DiI-LDL, 1,1'-dioctadecyl-3,3,3',3'-tetramethyl-indocarbocyanine perchlorate-labeled human LDL; ERK, extracellular signal-regulated kinase; IL-1β, interleukin-1β; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; MK2, mitogen-activated protein kinase-activated protein kinase 2; PKC, protein kinase C; qRT-PCR, quantitative RT-PCR; siRNA, small interfering RNA; SREBP, sterol-regulatory element binding protein; TPA, 12-O-tetradecanoyl-phorbol-13-acetate; TTP, tristetraprolin; UTR, untranslated region

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