Role of Mitogen-Activated Protein Kinases and Protein Kinase C in Regulating Low-Density Lipoprotein Receptor Expression

Author: MEHTA K.D.

Source: Gene Expression, Volume 10, Number 4, 2002 , pp. 153-164(12)

Publisher: Cognizant Communication Corporation

Abstract:

The cell signaling pathways that culminate in induction of low-density lipoprotein (LDL) receptor transcription in response to a variety of extracellular and intracellular signals are beginning to be defined. Evidence is accumulating that LDL receptor transcription is under complex regulation and that a major pathway of induction by cytokines, growth factors, anisomycin, and phorbol esters involves the extracellular/mitogen-activated protein kinase (p42/44^MAPK) cascade. In fact, degree of p42/44^MAPK activation determines the extent of LDL receptor induction. The suppression of LDL receptor expression by stress-activated p38^MAPK via p42/44^MAPK provides a potential mechanism for stress-induced hypercholesterolemia observed in humans and animals. Moreover, endogenous signals such as cholesterol regulate LDL receptor transcription through a different signaling cascade involving protein kinase C isoform (PKC). The ability of cholesterol to directly bind PKC in an isoform-specific manner strongly supports its role in sensing the cellular cholesterol levels. The emerging picture from the above studies is that regulation of LDL receptor transcription results from the activity of a number of interlinked regulatory molecules and pathways, rather than from a single linear series of events. These studies will provide the necessary framework for understanding differential responses within human populations to atherosclerosis following high-fat/cholesterol diet. This information may also provide new strategies to modulate specific gene expression with the hope to develop novel therapies for the treatment of hypercholesterolemia.

Keywords: p42/44MAPK p38MAPK Protein kinase C LDL receptor Transcriptional regulation Hepatic cells

Language: English

Document Type: Research article

Affiliations: 1: Department of Molecular and Cellular Biochemistry, Ohio State University College of Medicine and Public Health, 1645 Neil Avenue, Columbus, OH 43210

Publication date: 2002-01-01

• The Molecular and Cellular Biology area of Gene Expression covers all aspects of the gene including it structure, functions, and regulation in prokaryotes, eukaryotes, and viruses; molecular and cell biological aspects of cell growth and development, chromatin structure and function. These include topics such as DNA replication, DNA repair, gene transcription, transcriptional control, RNA processing, posttranscriptional control, oncogenes, molecular mechanisms of action of hormones, molecular mechanism of cellular differentiation, growth and development, protein synthesis, and posttranslational control.
  The Molecular and Cellular Neuroscience area of Gene Expression covers all aspects of gene expression as described but is devoted exclusively to the nervous system in health and disease. Topics include studies of neurogenesis, development, aging, and neurodegeneration. Complex neural systems, motor control, special senses, and higher cortical function, when viewed from the perspective of gene expression, are appropriate for the journal. Research related to molecular mechanisms of drug tolerance, dependence, and withdrawal are solicited. Manuscripts on state-of-the-art methods and protocols for molecular profiling of neuronal structure and function are welcome.

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• By this author: MEHTA K.D.

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