CELLULAR EFFECTS OF OLOMOUCINE, AN INHIBITOR OF CYCLIN-DEPENDENT KINASES
CELLULAR EFFECTS OF OLOMOUCINE, AN INHIBITOR OF CYCLIN-DEPENDENT KINASES
复制标题
DOI：
10.1016/0248-4900(96)81298-6
复制
发表时间：
1995-01-01
影响因子：
2.7
通讯作者：
VERLHAC, MH
中科院分区：
文献类型：
--
作者：
ABRAHAM, RT;ACQUARONE, M;VERLHAC, MH
Olomoucine (2-(2-羟乙基氨基)-6-苄氨基-9-甲基嘌呤) 最近被描述为细胞周期调节 p34(cdc2)/cyclin B、p33(cdk2)/cyclin A 和 p33(cdk2)/cyclin E 激酶、大脑 p33(cdk5)/p35 激酶和 ERK1/MAP 激酶的竞争性抑制剂（ATP 结合位点）。该化合物对细胞周期调节酶的特异性表明它可以抑制细胞周期的某些步骤。在多种植物和动物模型中研究了奥洛穆辛的细胞作用。该化合物抑制单细胞藻类（甲藻和硅藻）的 G1/S 转变。它阻止墨角藻合子分裂和海带配子体的发育。受刺激的矮牵牛叶肉原生质体在 G1 中被奥洛穆辛 (olomoucine) 抑制。通过阻止卵裂，它可以阻止桡足类幼虫的发育。它可逆地抑制秀丽隐杆线虫胚胎和海鞘胚胎的早期分裂。 Olomoucine 抑制 5-羟色胺诱导的蛤卵母细胞的前期/中期转变；此外，它还触发这些卵母细胞从减数分裂中期 I 停滞中释放出来，并诱导细胞核重组。奥洛穆辛减缓海胆胚胎分裂的前期/中期转变，但不影响中期/后期和后期/末期转变的持续时间。它还抑制由各种激动剂触发的海星卵母细胞的前期/中期转变。奥洛穆辛抑制非洲爪蟾卵母细胞的成熟、体内和体外伸长因子 EF-1 的磷酸化。该化合物可延迟小鼠卵母细胞的成熟，同时促进中期 II 停滞的孤雌生殖释放。 olomoucine 抑制多种人类细胞系（横纹肌肉瘤细胞系 Rh1、Rh18、Rh28 和 Rh30；MCF-7、KB-3-1 及其阿霉素耐药对应物国家癌症研究所 60 种人类肿瘤细胞系，包括九种肿瘤类型）的生长。非小细胞肺癌细胞系 MR65 的细胞周期参数分析表明，olomoucine 影响 G1 和 S 期转变。 Olomoucine 抑制白细胞介素 2 刺激的 T 淋巴细胞（CTLL-2 细胞）中的 DNA 合成，并触发类似于白细胞介素 2 剥夺的 G1 期阻滞。 cdc2 和 cdk2 激酶（分别从诺考达唑和羟基脲处理的 CTLL-2 细胞中免疫沉淀）均被 olomoucine 抑制。酵母和果蝇胚胎均对奥洛穆辛不敏感。总而言之，这种诺亚方舟方法的结果表明，olomoucine 在 G1/S 和 G2/M 边界处阻滞细胞，这与分别对 cdk2 和 cdc2 激酶产生普遍影响的假设一致。
Olomoucine (2-(2-hydroxyethylamino)-6-benzylamino-9-methylpurine) has been recently described as a competitive inhibitor (ATP-binding site) of the cell cycle regulating p34(cdc2)/cyclin B, p33(cdk2)/cyclin A and p33(cdk2)/cyclin E kinases, the brain p33(cdk5)/p35 kinase and the ERK1/MAP-kinase, The unusual specificity of this compound towards cell cycle regulating enzymes suggests that it could inhibit certain steps of the cell cycle. The cellular effects of olomoucine were investigated in a large variety of plant and animal models. This compound inhibits the G1/S transition of unicellular algae (dinoflagellate and diatom). It blocks Fucus zygote cleavage and development of Laminaria gametophytes. Stimulated Petunia mesophyl protoplasts are arrested in G1 by olomoucine. By arresting cleavage it blocks the development of Calanus copepod larvae. It reversibly inhibits the early cleavages of Caenorhabditis elegans embryos and those of ascidian embryos. Olomoucine inhibits the serotonin-induced prophase/metaphase transition of clam oocytes; furthermore, it triggers the release of these oocytes from their meiotic metaphase I arrest, and induces nuclei reformation. Olomoucine slows down the prophase/metaphase transition in cleaving sea urchin embryos, but does not affect the duration of the metaphase/anaphase and anaphase/telophase transitions. It also inhibits the prophase/metaphase transition of starfish oocytes triggered by various agonists. Xenopus oocyte maturation, the in vivo and in vitro phosphorylation of elongation factor EF-1 are inhibited by olomoucine. Mouse oocyte maturation is delayed by this compound, whereas parthenogenetic release from metaphase II arrest is facilitated. Growth of a variety of human cell lines (rhabdomyosarcoma cell lines Rh1, Rh18, Rh28 and Rh30; MCF-7, KB-3-1 and their adriamycin-resistant counterparts National Cancer Institute 60 human tumor cell lines comprising nine tumor types) is inhibited by olomoucine. Cell cycle parameter analysts of the non-small cell lung cancer cell line MR65 shows that olomoucine affects G1 and S phase transits. Olomoucine inhibits DNA synthesis in interleukin-2-stimulated T lymphocytes (CTLL-2 cells) and triggers a G1 arrest similar to interleukin-2 deprivation. Both cdc2 and cdk2 kinases (immunoprecipitated from nocodazole- and hydroxyurea-treated CTLL-2 cells, respectively) are inhibited by olomoucine. Both yeast and Drosophila embryos were insensitive to olomoucine. Taken together the results of this Noah's Ark approach show that olomoucine arrests cells both at the G1/S and the G2/M boundaries, consistent with the hypothesis of a prevalent effect on the cdk2 and cdc2 kinases, respectively.