Peffley D, Miyake J, Leonard S, von Gunten C, Sinensky M
Eleanor Roosevelt Institute for Cancer Research, Denver, Colorado 80206.
Somat Cell Mol Genet. 1988 Nov;14(6):527-39. doi: 10.1007/BF01535308.
Two enzymes of mammalian cellular mevalonate biosynthesis, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase and HMG-CoA reductase, have been shown to be regulated by exogenous sterols. It has been demonstrated that these enzymes are regulated, at least in part, by transcriptional control of their synthesis. We have previously described a somatic cell mutant (CR1) of the CHO-K1 cell line that is defective in regulation of the activity of these enzymes in response to exogenous sterols. In this report, we demonstrate that this mutant is defective in regulation of the mRNA levels for HMG-CoA reductase and HMG-CoA synthase by 25-hydroxycholesterol and mevinolin. In the case of HMG-CoA reductase, this loss of apparent transcriptional control is not accompanied by a comparable loss in regulation of synthesis of this enzyme. This observation is consistent with prior studies suggesting that HMG-CoA reductase can be regulated translationally. We also show that CR1 cells exhibit a constitutively rapid rate of degradation of HMG-CoA reductase.
哺乳动物细胞甲羟戊酸生物合成途径中的两种酶，3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）合酶和HMG-CoA还原酶，已被证明受外源固醇调节。已证实这些酶至少部分受其合成的转录控制。我们之前描述过CHO-K1细胞系的一个体细胞突变体（CR1），该突变体对外源固醇应答时这些酶活性的调节存在缺陷。在本报告中，我们证明该突变体在25-羟基胆固醇和洛伐他汀对HMG-CoA还原酶和HMG-CoA合酶mRNA水平的调节方面存在缺陷。就HMG-CoA还原酶而言，这种明显转录控制的丧失并未伴随该酶合成调节的类似丧失。这一观察结果与先前的研究一致，表明HMG-CoA还原酶可受翻译水平调节。我们还表明，CR1细胞表现出HMG-CoA还原酶持续快速降解的速率。
