Genes that overcome drug-induced cholesterol auxotrophy

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Publication Type dissertation
School or College School of Medicine
Department Human Genetics
Author Mykytyn, Kirk Allen
Title Genes that overcome drug-induced cholesterol auxotrophy
Date 1999-12
Description Mammalian cells obtain cholesterol via endocytic uptake of cholesterol-rich lipoproteins and de novo synthesis through a multistep pathway. However, excess cholesterol is deleterious and cellular cholesterol levels must be strictly regulated. This regulation involves a complex set of homeostatic processes. Understanding the mechanisms involved in this regulation has implications for heart disease as well as developmental disorders. We have used a novel system for studying the effects of cholesterol synthesis inhibitors on development using zebrafish. We find that progesterone inhibits cholesterol synthesis in vitro and causes developmental abnormalities in embryos that can be prevented by the addition of water-soluble cholesterol. These findings demonstrate that cholesterol is necessary for proper development in zebrafish. Previous studies have shown that treating pregnant rats with AY-9944, a pharmacologic inhibitor of the final enzyme in the cholesterol biosynthesis pathway, causes birth defects. We find that AY-9944 confers cholesterol auxotrophy in Chinese hamster ovary (CHO) cells. We used this inhibitor in an expression cloning approach and isolated two genes that overcome AY-9944-induced cholesterol auxotrophy, when overexpressed. The first gene we isolated from this screen is subunit 3 of the COP9 signalosome sgn3. We show that this gene is most highly expressed in heart and skeletal muscle, maps to human chromosome 17p11.1-p11.2, and is deleted in all patients with the developmental disorder Smith-Magenis syndrome (SMS). These observations suggest a role for SGN3 and the COP9 signalosome in cholesterol metabolism as well as SMS. The second gene we isolated is HDL-binding protein (HBP), which is also known as vigilin. We show that cells overexpressing HBP/vigilin display no difference in cholesterol metabolism, but have an increase in fatty acid synthesis. Furthermore, we find that HBP/vigilin transcription is regulated by the nuclear hormone receptor PPAR?. These findings support a function for HBP/vigilin in fatty acid synthesis and raise the possibility that it plays a role in the adipogenic pathway.
Type Text
Publisher University of Utah
Subject Genetics; Physiopathology
Subject MESH Cholesterol; Zeatin
Dissertation Institution University of Utah
Dissertation Name PhD
Language eng
Relation is Version of Digital reproduction of "Genes that overcome drug-induced cholesterol auxotrophy." Spencer S. Eccles Health Sciences Library. Print version of "Genes that overcome drug-induced cholesterol auxotrophy." available at J. Willard Marriott Library Special Collection. QP6.5 1999 .M94.
Rights Management © Kirk Allen Mykytyn.
Format Medium application/pdf
Format Extent 3,359,072 bytes
Identifier undthes,5285
Source Original: University of Utah Spencer S. Eccles Health Sciences Library (no longer available).
Master File Extent 3,359,092 bytes
ARK ark:/87278/s6222wnv
Setname ir_etd
Date Created 2012-04-24
Date Modified 2021-05-06
ID 191783
Reference URL
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