Glesne D A, Collart F R, Huberman E
Biological and Medical Research Division, Argonne National Laboratory, Illinois 60439.
Mol Cell Biol. 1991 Nov;11(11):5417-25. doi: 10.1128/mcb.11.11.5417-5425.1991.
To study the regulation of IMP dehydrogenase (IMPDH), the rate-limiting enzyme of guanine nucleotide biosynthesis, we examined the effects of nucleosides, nucleotides, nucleotide analogs, or the IMPDH inhibitor mycophenolic acid (MPA) on the steady-state levels of IMPDH mRNA. The results indicated that IMPDH gene expression is regulated inversely by the intracellular level of guanine ribonucleotides. We have shown that treatment with guanosine increased the level of cellular guanine ribonucleotides and subsequently reduced IMPDH steady-state mRNA levels in a time- and dose-dependent manner. Conversely, MPA treatment diminished the level of guanine ribonucleotides and increased IMPDH mRNA levels. Both of these effects on the steady-state level of IMPDH mRNA could be negated by cotreatment with guanosine and MPA. The down regulation of IMPDH gene expression by guanosine or its up regulation by MPA was not due to major changes in transcriptional initiation and elongation or mRNA stability in the cytoplasm but rather was due to alterations in the levels of the IMPDH mRNA in the nucleus. These results suggest that IMPDH gene expression is regulated by a posttranscriptional, nuclear event in response to fluctuations in the intracellular level of guanine ribonucleotides.
为了研究鸟嘌呤核苷酸生物合成的限速酶肌苷酸脱氢酶（IMPDH）的调控机制，我们检测了核苷、核苷酸、核苷酸类似物或IMPDH抑制剂霉酚酸（MPA）对IMPDH mRNA稳态水平的影响。结果表明，IMPDH基因表达受鸟嘌呤核糖核苷酸细胞内水平的反向调控。我们发现，用鸟苷处理可提高细胞内鸟嘌呤核糖核苷酸水平，并随后以时间和剂量依赖的方式降低IMPDH稳态mRNA水平。相反，MPA处理可降低鸟嘌呤核糖核苷酸水平并提高IMPDH mRNA水平。鸟苷和MPA共同处理可消除这两种对IMPDH mRNA稳态水平的影响。鸟苷对IMPDH基因表达的下调或MPA对其的上调并非由于转录起始和延伸或细胞质中mRNA稳定性的重大变化，而是由于细胞核中IMPDH mRNA水平的改变。这些结果表明，IMPDH基因表达受转录后核事件调控，以响应细胞内鸟嘌呤核糖核苷酸水平的波动。
