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Journal of Lipid Research, Vol. 44, 584-593, March 2003
Copyright © 2003 by Lipid Research, Inc.

pp90^RSK- and protein kinase C-dependent pathway regulates p42/44^MAPK-induced LDL receptor transcription in HepG2 cells

Gurpreet S. Kapoor¹, Carmen Golden, Brett Atkins² and Kamal D. Mehta³

Department of Molecular and Cellular Biochemistry, The Ohio State University College of Medicine and Public Health, 464 Hamilton Hall, 1645 Neil Ave., Columbus, OH 43210

¹ Present address of G. S. Kapoor: Department of Neurosurgery, The University of Pennsylvania School of Medicine, 36^th and Spruce St., Philadelphia, PA 19104

We have previously shown that different extracellular stimuli require signaling through the Raf/MEK/p42/44^MAPK cascade to induce LDL receptor expression. The present studies were designed to delineate the molecular mechanisms underlying p42/44^MAPK-induced LDL receptor transcription in HepG2-Raf-1:ER cells, a modified HepG2 cell line in which the Raf-1/MEK/p42/44^MAPK cascade can be specifically activated by anti-estradiol ICI182,780 in an agonist-specific manner. Using these cells, we show that: a) LDL receptor induction was reduced in reporter constructs containing mutation in either Sp1 or sterol-regulatory element-1 (SRE-1) sites, whereas inactivation of both sites abolished the induction; b) E1A, which inhibits CREB binding protein (CBP), a common activator of SRE-1 binding protein and Sp1, strongly repressed the induction; c) intracellular inhibition of the 90 kDa ribosomal S6 kinase (pp90^RSK) cascade reduced LDL receptor induction; d) highly selective protein kinase C (PKC) inhibitors effectively abrogated the induction without affecting activation of pp90^RSK; and e) overexpression of PKCß significantly induced LDL receptor promoter activity.

Taken together, these results demonstrate that pp90^RSK and PKCß are downstream effectors and Sp1, SRE-1 binding protein, and CBP are part of the transcriptional complex resulting in induction of LDL receptor expression in response to activation of the Raf/MEK/p42/44^MAPK cascade. These findings identify for the first time a role for PKCß in determining the specificity of p42/44^MAPK signaling by participating with pp90^RSK in regulating gene expression.

Abbreviations: CBP, CREB binding protein; CREB, cAMP response element binding protein; ICI182,780, (7-[9-[(4,4,5,5,5,-pentafluoropentyl) sulfinyl]nonyl]-estra-1,3,5(10)-triene-3,17ß-diol; LPDS, lipoprotein-deficient serum; MAPK, mitogen-activated protein kinase; p42/44^MAPK, extracellular signal-regulated kinase; PKC, protein kinase C; pp90^RSK, 90 kDa ribosomal S6 kinase; SRE, sterol regulatory element; SREBP, SRE binding protein; WT, wild type

Supplementary key words 90 kDa ribosomal S6 kinase • extracellular signal-regulated kinase • CREB binding protein

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