CELL-DIFFERENTIATION AND ALTERED IMP DEHYDROGENASE EXPRESSION INDUCED IN HUMAN T-LYMPHOBLASTOID LEUKEMIA-CELLS BY MYCOPHENOLIC-ACID AND TIAZOFURIN
CELL-DIFFERENTIATION AND ALTERED IMP DEHYDROGENASE EXPRESSION INDUCED IN HUMAN T-LYMPHOBLASTOID LEUKEMIA-CELLS BY MYCOPHENOLIC-ACID AND TIAZOFURIN
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DOI：
10.1016/0014-4827(90)90114-p
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发表时间：
1990-03-01
影响因子：
3.7
通讯作者：
HUBERMAN, E
中科院分区：
文献类型：
--
作者：
KIGUCHI, K;COLLART, FR;HUBERMAN, E
IMP脱氢酶抑制剂霉酚酸（MPA）和噻唑呋喃（TZ）对t淋巴样CEM-2白血病细胞的生长和分化具有时间和剂量依赖性的抑制作用。分化的细胞获得了抑制/细胞毒性t淋巴细胞表型，其特征是与成熟特异性单克隆抗体反应性。鸟苷和次黄嘌呤的共同施用可以减轻MPA或TZ对生长的抑制和诱导分化。在CEM-2细胞中，另一种抑制/细胞毒性表型的诱诱剂phorbol 12-肉豆蔻酸13-乙酸酯（PMA）诱导的分化未观察到这种减少。在MPA或TZ治疗的前2天，观察到稳定的IMPDH mRNA水平和细胞酶量增加的模式，可能是因为抑制剂介导的细胞IMPDH活性降低或MPA或TZ介导的IMPDH蛋白水解减少的补偿。PMA处理降低了IMPDH mRNA、蛋白水平和活性。此外，用IMPDH抑制剂或PMA处理CEM-2细胞会引起核糖核苷酸池的不同改变。在使用IMPDH抑制剂或PMA处理的CEM-2细胞中，缺乏一致的IMPDH表达模式表明，诱导细胞分化与IMPDH表达之间不存在普遍关联。然而，我们的研究结果表明，IMPDH抑制剂可以诱导CEM-2细胞分化，这表明这种治疗可能提供了一种有效的方法来绕过某些肿瘤细胞的分化障碍。
The IMP dehydrogenase inhibitors mycophenolic acid (MPA) and tiazofurin (TZ) induce a time- and dose-dependent inhibition of cell growth, as well as differentiation in T-lymphoid CEM-2 leukemia cells. The differentiated cells have acquired a suppressor/cytotoxic T-lymphocyte phenotype characterized by reactivity with maturation-specific monoclonal antibodies. Coadministration of guanosine and hypoxanthine reduces the growth inhibition and diminishes the induction of differentiation by either MPA or TZ. No such reduction was observed for differentiation induced by phorbol 12-myristate 13-acetate (PMA), another inducer of a suppressor/cytotoxic phenotype in CEM-2 cells. During the first 2 days of treatment with MPA or TZ, a pattern of stable IMPDH mRNA levels and increased amounts of cellular enzyme was observed, perhaps, because of compensation for the inhibitor-mediated decrease in cellular IMPDH activity or a MPA- or TZ-mediated decrease in proteolysis of IMPDH. PMA treatment decreased the levels of IMPDH mRNA, protein, and activity. In addition, treatment of CEM-2 cells with either IMPDH inhibitors or PMA caused different alterations of the ribonucleotide pools. The lack of a consistent pattern of IMPDH expression in CEM-2 cells treated with IMPDH inhibitors or PMA indicates that no general association exists between the induction of cell differentiation and the expression of IMPDH. Nevertheless, our results indicating that IMPDH inhibitors can induce differentiation in CEM-2 cells suggest that this treatment may provide a useful approach to circumvent the differentiation block in some tumor cells.