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首页> 外文期刊>Molecular and Cellular Biology >Transcriptional regulation of the human CAD gene during myeloid differentiation.
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Transcriptional regulation of the human CAD gene during myeloid differentiation.

机译：骨髓分化过程中人类CAD基因的转录调控。

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摘要

CAD codes for a trifunctional protein involved in the catalysis of the first three enzymatic activities in the de novo pyrimidine biosynthetic pathway, namely, carbamoyl-phosphate synthetase II (EC 6.3.5.5), aspartate transcarbamylase (EC 2.1.3.2), and dihydroorotase (EC 3.5.2.3). CAD regulation was studied in the human promyelocyte leukemic line HL-60 as it differentiated into monocytic or granulocytic lineages after induction by 12-O-tetradecanoylphorbol-13-acetate or trans-retinoic acid and dibutyryl cyclic AMP, respectively. Within 12 h of induction of HL-60 cells with either inducer, total cellular levels of CAD RNA essentially disappeared. On the other hand, no apparent decreases in beta-actin RNA levels were seen even 48 h after HL-60 cells were induced, as compared with untreated cells. With nuclear runoff assays, it was clearly shown that the inactivation of CAD gene expression during the induction of HL-60 cells with either inducer was at the transcriptional level. The nuclear runoff experiments also demonstrated that the CAD gene expression was shut down in less than 4 h after induction, well before morphological changes were observed in these cells. At the enzymatic level, the activity of aspartate transcarbamylase, one of the three enzymes encoded by the CAD gene, decreased by about half within 24 h of induction, suggesting a CAD protein half-life of 24 h in differentiating HL-60 cells. Nevertheless, this means that significant levels of aspartate transcarbamylase activity remained even after the cells have stopped proliferating. From the RNA data, it is clear that CAD gene expression is rapidly turned off as promyelocytes begin to terminally differentiate into macrophages and granulocytes. We suspect that the inactivation of the CAD gene in induced HL-60 cells is a consequence of the differentiating cells leaving the cell cycle and becoming nonproliferating.
机译：CAD编码在从头嘧啶生物合成途径的前三个酶催化中涉及的三功能蛋白，即氨基甲酰基磷酸合成酶II（EC 6.3.5.5），天冬氨酸转氨甲酰酶（EC 2.1.3.2）和二氢乳清酶EC 3.5.2.3）。在人类早幼粒细胞白血病系HL-60中研究了CAD调节，因为它在分别被12-O-十四烷酰phorbol-13-乙酸盐或反式视黄酸和二丁酰基环状AMP诱导后分化为单核或粒细胞谱系。在用任一诱导剂诱导HL-60细胞诱导12小时内，CAD RNA的总细胞水平基本消失。另一方面，与未处理的细胞相比，即使在诱导HL-60细胞后48小时，β-肌动蛋白RNA水平也没有明显降低。用核径流测定法清楚地表明，用任一诱导物诱导HL-60细胞期间，CAD基因表达的失活处于转录水平。核径流实验还表明，在诱导后不到4 h内，即在这些细胞中观察到形态变化之前，CAD基因表达就被关闭了。在酶促水平上，由CAD基因编码的三种酶之一的天冬氨酸转氨甲酰酶的活性在诱导后24小时内下降了约一半，这表明在分化的HL-60细胞中，CAD蛋白的半衰期为24小时。尽管如此，这意味着即使细胞已经停止增殖后，仍然存在显着水平的天冬氨酸转氨酶活性。从RNA数据可以明显看出，随着早幼粒细胞开始最终分化为巨噬细胞和粒细胞，CAD基因表达迅速被关闭。我们怀疑诱导的HL-60细胞中CAD基因的失活是分化细胞离开细胞周期并变得不增殖的结果。

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