Selective up-regulation of type II inosine 5'-monophosphate dehydrogenase messenger RNA expression in human leukemias.
Selective up-regulation of type II inosine 5'-monophosphate dehydrogenase messenger RNA expression in human leukemias.
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发表时间：
1991-08
期刊：
影响因子：
11.2
通讯作者：
Masami Nagai;Y. Natsumeda;Yasuhiko Konno;Ronald Hoffman;Shozo Irino;George Weber
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作者：
Masami Nagai;Y. Natsumeda;Yasuhiko Konno;Ronald Hoffman;Shozo Irino;George Weber
IMP脱氢酶（IMPDH; EC 1.1.1.205）是GTP从头生物合成的限速酶，其同工酶（I型和II型）的发现作为癌症诊断和选择性肿瘤细胞化疗的可能的新方法而引起关注。为了阐明两种IMPDH同工酶表达和调节的差异，我们检测了来自患者的各种类型白血病细胞中这些mRNA的稳态水平。北方印迹分析表明，II型IMPDH是更积极的转录（1.5至5.1倍），在所有的白血病细胞检查比在正常淋巴细胞，而I型的表达是相似的。白血病细胞中II型mRNA表达的增加与总IMPDH活性的增加密切相关（r = 0.92）。当白血病细胞从患者的慢性粒细胞白血病在原始细胞危象分离成胚丰富和成熟的白细胞丰富的部分，II型mRNA的表达呈正相关的人口不成熟的白血病细胞，而I型表达不变。用12-O-十四酰基-佛波醇-13-乙酸酯处理白血病原始细胞5天，导致具有巨噬细胞样分化的II型mRNA表达下降90%，而I型mRNA表达相对稳定。这些观察结果表明，II型IMPDH的表达与白血病细胞的不成熟特征密切相关，因此，它应该是抗白血病化疗的选择性靶点。
The discovery of isozymes (types I and II) of IMP dehydrogenase (IMPDH; EC 1.1.1.205), the rate-limiting enzyme of de novo GTP biosynthesis, has attracted attention as a possible novel approach to cancer diagnosis and selective tumor cell chemotherapy. To elucidate differences in expression and regulation of the two IMPDH isozymes, we examined the steady-state levels of these mRNAs in various types of leukemic cells from patients. Northern blot analysis revealed that type II IMPDH was more active transcriptionally (1.5- to 5.1-fold) in all the leukemic cells examined than in normal lymphocytes, whereas type I expression was similar. The increased expression of type II mRNA in leukemic cells was closely linked with the increase in total IMPDH activity (r = 0.92). When leukemic cells from a patient with chronic granulocytic leukemia in blast crisis were separated into blast-rich and mature leukocyte-rich fractions, the expression of type II mRNA correlated positively with the population of immature leukemic cells, whereas type I expression was unchanged. Treatment of leukemic blasts with 12-O-tetradecanoyl-phorbol-13-acetate for 5 days resulted in a 90% decrease in the expression of type II mRNA with macrophage-like differentiation, while the expression of type I mRNA was relatively stable. These observations suggest that expression of type II IMPDH is stringently linked with immature characteristics of leukemic cells; thus, it should be a selective target for antileukemic chemotherapy.