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J. Biol. Chem., Vol. 263, Issue 18, 8929-8937, 06, 1988
M Nakanishi, JL Goldstein and MS Brown
The enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA
reductase) is subject to multivalent feedback suppression mediated by
sterols and non-sterol substances derived from mevalonate, the product of
the enzyme. To dissect the mechanism for this multivalent effect, Chinese
hamster ovary cells were incubated with sterols contained in plasma
lipoproteins and with a high concentration (100 microM) of compactin, an
inhibitor of the reductase. Under these conditions, the amounts of HMG-CoA
reductase protein and catalytic activity were high, although the cells were
saturated with sterols, as reflected by active synthesis of cholesteryl
esters. The amount of enzyme fell by 99% when the cells received excess
mevalonate in addition to sterols. This decline was not associated with a
fall in levels of reductase messenger RNA (mRNA). Rather, it was
attributable to an 80% decline in translation of the mRNA, coupled with a
5-fold increase in the rate of degradation of reductase protein, as
revealed by pulse-chase experiments with [35S]methionine. Considered
together with previous data, these findings suggest a multilevel mechanism
for multivalent regulation of HMG-CoA reductase. We suggest that sterols
suppress the enzyme incompletely by partially repressing transcription of
the gene and that nonsterol products derived from mevalonate further reduce
the enzyme by inhibiting translation of the mRNA. Sterols and non-sterol
products, acting together, accelerate the degradation of reductase protein.
This combination of transcriptional and posttranscriptional controls can
regulate the amount of reductase protein over a several hundred-fold range
in animal cells.
Multivalent control of 3-hydroxy-3-methylglutaryl coenzyme A reductase. Mevalonate-derived product inhibits translation of mRNA and accelerates degradation of enzyme
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas 75235.
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