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Molecular and Cellular Biology, June 2002, p. 3783-3793, Vol. 22, No. 11
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.11.3783-3793.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Critical Role of Diacylglycerol- and Phospholipid-Regulated Protein Kinase C in Induction of Low-Density Lipoprotein Receptor Transcription in Response to Depletion of Cholesterol

Department of Molecular and Cellular Biochemistry, The Ohio State University College of Medicine, Columbus, Ohio 43210,¹ Department of Biochemistry and Molecular Biology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205²

Received 13 August 2001/ Returned for modification 21 September 2001/ Accepted 13 February 2002

Induction of low-density lipoprotein (LDL) receptor transcription in response to depletion of cellular sterols in animal cells is well established. The intracellular signal or signals involved in regulating this process, however, remain unknown. Using a specific inhibitor of protein kinase C (PKC), calphostin C, we show the requirement of this kinase in the induction process in human hepatoma HepG2 cells. Overexpression of PKC, but not PKC, -, -, or - was found to dramatically induce (approximately 18-fold) LDL receptor promoter activity. Interestingly, PKC-mediated induction was found to be sterol resistant. To further establish that PKC is involved in the sterol regulation of LDL receptor gene transcription, endogenous PKC was specifically inhibited by transfection with antisense PKC phosphorothionate oligonucleotides. Antisense treatment decreased endogenous PKC protein levels and completely blocked induction of LDL receptor transcription following sterol depletion. PKC-induced LDL receptor transcription is independent of the extracellular signal-regulated kinase 1 and 2 (p42/44^MAPK) cascade, because the MEK-1/2 inhibitor, PD98059 did not inhibit, even though it blocked p42/44^MAPK activation. Finally, photoaffinity labeling studies showed an isoform-specific interaction between PKC and sterols, suggesting that sterols may directly modulate its function by hampering binding of activators. This was confirmed by PKC activity assays. Altogether, these results define a novel signaling pathway leading to induction of LDL receptor transcription following sterol depletion, and a model is proposed to account for a new function for PKC as part of a sterol-sensitive signal transduction pathway in hepatic cells.

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