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Papers In Press, published online ahead of print January 1, 2003
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Molecular and Cellular Biochemistry, Ohio State University College of Medicine and Public Health, Columbus, OH 43210
Corresponding Author: mehta.80{at}osu.edu
We have previously shown that different extracellular stimuli require signaling through raf/MEK/p42/44MAPK cascade to induce LDL receptor expression. The present studies were designed to delineate the molecular mechanisms underlying p42/44MAPK-induced LDL receptor transcription in HepG2-deltaRaf-1:ER cells, a modified HepG2 cell line in which Raf-1/MEK/p42/44MAPK 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-responsive 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 pp90RSK cascade reduced LDL receptor induction; (d) highly selective PKC inhibitors effectively abrogated the induction without affecting activation of pp90RSK; (e) overexpression of PKCbeta significantly induced LDL receptor promoter activity. Taken together, these results demonstrate that pp90RSK and sterol-sensitive PKCbeta 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 Raf/MEK/p42/44MAPK cascade. These findings identify for the first time a role for PKCbeta in determining the specificity of p42/44MAPK signaling by participating with pp90RSK in regulating gene expression.
Revised on November 7, 2002
Accepted on December 16, 2002
pp90RSK- and protein kinase C
-dependent pathway regulates p42/44MAPK-induced LDL receptor transcription in HepG2 cells
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