Complementary recessive 25‐hydroxycholesterol‐resistant somatic cell mutants – assay of 25‐hydroxycholesterol binding activity

Sinensky, Michael; Logel, Judith; Torget, Robert

doi:10.1002/jcp.1041130220

Cited by 20 publications

(5 citation statements)

References 26 publications

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“…We called these cells sterol regulatory-defective (SRD-1, -2, and -3) cells (25,26). Similar sterolresistant cell lines were reported from the laboratories of Kandutsch (27), Sinensky (28,29), and Chang (30,31).…”

Section: Mutant Mammalian Cells With Defects In Cholesterol Homeostassupporting

confidence: 81%

Mutant Mammalian Cells as Tools to Delineate the Sterol Regulatory Element-Binding Protein Pathway for Feedback Regulation of Lipid Synthesis

Goldstein

Rawson

Brown

2002

Archives of Biochemistry and Biophysics

220

161

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Section: Mutant Mammalian Cells With Defects In Cholesterol Homeostassupporting

confidence: 81%

Mutant Mammalian Cells as Tools to Delineate the Sterol Regulatory Element-Binding Protein Pathway for Feedback Regulation of Lipid Synthesis

Goldstein

Rawson

Brown

2002

Archives of Biochemistry and Biophysics

220

161

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“…This is further extended by the results discussed below, but is also in agreement with effects observed in rat liver, where mevinolin (an analogue of compactin; Alberts et al, 1980) increased (Clarke et al, 1983) and mevalonate decreased (Clarke et al, 1984) the reductase mRNA content, whereas mevalonate enhanced the enzyme degradation . Further, it was noted that mevinolin prevented HMG-CoA reductase enzyme degradation in Chinese-hamster ovary cells (Sinensky & Logel, 1983). Comparable effects of compactin and mevalonate on reductase mRNA contents were measured in UT-I cells (Luskey et al, 1983), a Chinese-hamster ovary mutant cell line, resistant to compactin , by a stable amplification of the reductase gene (Luskey et al, 1983).…”

Section: Discussionmentioning

confidence: 99%

Regulation of 3-hydroxy-3-methylglutaryl-CoA reductase mRNA contents in human hepatoma cell line Hep G2 by distinct classes of mevalonate-derived metabolites

Cohen¹,

Griffioen²

1988

Biochemical Journal

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Hep G2 cells were incubated under conditions known to influence the HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) reductase activity, e.g. in the presence of compactin (a competitive inhibitor of HMG-CoA reductase itself) and U18666A (a squalene-2,3-epoxide cyclase inhibitor). We studied the effects of these conditions both on the HMG-CoA reductase activity and on the reductase mRNA content. In the presence of compactin the mRNA content increased, but less than the enzyme activity, as determined after removal of the inhibitor. The increase in mRNA could be prevented by addition of mevalonate or by a combination of low-density lipoprotein (LDL) plus a low concentration of mevalonate. LDL alone prevented the compactin-induced increases in mRNA and activity only partially. The effect of U18666A on reductase mRNA content and activity was biphasic, i.e. a slight decrease at low (0.3-0.5 microM) concentrations, with a concomitant formation of polar sterols [Boogaard, Griffioen & Cohen (1987) Biochem. J. 241, 345-351], and an increase at high (20-30 microM) concentrations, with complete blockage of sterol formation. At these high concentrations of U18666A, additional compactin (2 microM) increased the reductase activity, but not the mRNA content. We conclude that non-sterol metabolites of mevalonate regulate exclusively at the enzyme level, whereas sterol metabolites regulate at the reductase mRNA level. In the latter group of regulators we distinguish mevalonate metabolites which can, and metabolites which cannot, be replaced by exogenous LDL.

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“…Early somatic cell genetic characterization indicated that there was genetic diversity in such mutants and that some were recessive (13,14). The class 1 and 2 mutants, whose defects are now known, are dominant (or co-dominant) mutations.…”

mentioning

confidence: 99%

Oleate Potentiates Oxysterol Inhibition of Transcription from Sterol Regulatory Element-1-regulated Promoters and Maturation of Sterol Regulatory Element-binding Proteins

Thewke

Panini

Sinensky

1998

Journal of Biological Chemistry

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Activation of genes containing SRE-1 (sterol regulatory element 1) sequences is known to be under the regulation of sterols through modulation of the proteolytic maturation of SREBPs (SRE-1-binding proteins). Previous work has demonstrated SREBP-mediated transcriptional activation of genes encoding enzymes of sterol and fatty acid biosynthesis. Because synthesis of both sterols and C18 fatty acids are required for cell growth, in the absence of exogenous supplements of these lipids, we examined the hypothesis that fatty acid can also be regulatory in SREBP maturation. Our data indicate that C18 fatty acids can potentiate the biological activities of a typical, regulatory sterol: 25-hydroxycholesterol. Inhibition of C18 fatty acid synthesis in cells cultured in serum-free medium renders them resistant to killing by 25-hydroxycholesterol. Repression of expression of reporter constructs driven by promoters bearing SRE-1 element(s) by 25-hydroxycholesterol is increased by C18 fatty acid supplementation. C18 fatty acids also increase the inhibitory effect of 25-hydroxycholesterol on proteolytic maturation and nuclear localization of SREBPs. Furthermore, we also show that C18 fatty acid supplementation can enhance the inhibitory effect of 25-hydroxycholesterol on sterol and fatty acid biosynthesis. These results demonstrate that maximal down-regulation of SREBP maturation and the consequent repression of SRE-1 promoters occurs in response to both a regulatory sterol and fatty acid.

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Complementary recessive 25‐hydroxycholesterol‐resistant somatic cell mutants – assay of 25‐hydroxycholesterol binding activity

Cited by 20 publications

References 26 publications

Mutant Mammalian Cells as Tools to Delineate the Sterol Regulatory Element-Binding Protein Pathway for Feedback Regulation of Lipid Synthesis

Mutant Mammalian Cells as Tools to Delineate the Sterol Regulatory Element-Binding Protein Pathway for Feedback Regulation of Lipid Synthesis

Regulation of 3-hydroxy-3-methylglutaryl-CoA reductase mRNA contents in human hepatoma cell line Hep G2 by distinct classes of mevalonate-derived metabolites

Oleate Potentiates Oxysterol Inhibition of Transcription from Sterol Regulatory Element-1-regulated Promoters and Maturation of Sterol Regulatory Element-binding Proteins

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