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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Effects of the tumor inhibitory triterpenoid avicin G on cell integrity, cytokinesis, and protein ubiquitination in fission yeast
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Effects of the tumor inhibitory triterpenoid avicin G on cell integrity, cytokinesis, and protein ubiquitination in fission yeast

机译：肿瘤抑制性三萜类阿维辛G对裂殖酵母中细胞完整性，胞质分裂和蛋白泛素化的影响

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摘要

Avicins comprise a class of triterpenoid compounds that exhibit tumor inhibitory activity. Here we show that avicin G is inhibitory to growth of the fission yeast Schizosaccharomyces pombe. S. pombe cells treated with a lethal concentration of avicin G (20 mu M) exhibited a shrunken morphology, indicating that avicin G adversely affects cell integrity. Cells treated with a sublethal concentration of avicin G (6.5 mu M) exhibited a strong cytokinesis-defective phenotype (multiseptated cells), as well as cell morphology defects. These phenotypes bear resemblance to those resulting from loss of Rho1 GTPase function in S. pombe. Indeed, Rho1-deficient S. pombe cells were strongly hypersensitive to avicin G, suggesting that the compound may perturb Rho1-dependent processes. Consistent with previously observed effects in human Jurkat T cells, avicin G treatment resulted in hyperaccumulation of ubiquitinated proteins in S. pombe cells. Interestingly, proteasome-defective S. pombe mutants were not markedly hypersensitive to avicin G, whereas an anaphase-promoting complex (mitotic ubiquitin ligase) mutant exhibited avicin G resistance, suggesting that the increase in levels of ubiquitinated proteins resulting from avicin G treatment may be due to increased protein ubiquitination, rather than inhibition of 26S proteasome activity. Mutants defective in the cAMP/PKA pathway also exhibited resistance to avicin G. Our results suggest that S. pombe will be a useful model organism for elucidating molecular targets of avicin G and serve as a guide to clinical application where dysfunctional aspects of Rho and/or ubiquitination function have been demonstrated as in cancer, fibrosis, and inflammation.
机译：阿维菌素包含一类显示肿瘤抑制活性的三萜类化合物。在这里，我们显示了阿维菌素G对裂殖酵母粟酒裂殖酵母的生长具有抑制作用。用致死浓度的阿维菌素G（20μM）处理的粟酒裂殖酵母细胞表现出收缩的形态，表明阿维菌素G对细胞完整性有不利影响。亚致死浓度的阿维菌素G（6.5μM）处理的细胞表现出强的胞质分裂缺陷型表型（多肽细胞），以及细胞形态缺陷。这些表型类似于由粟酒裂殖酵母中Rho1 GTPase功能丧失引起的表型。确实，缺乏Rho1的粟酒裂殖酵母细胞对阿维菌素G高度敏感，表明该化合物可能会扰乱Rho1依赖性过程。与先前在人Jurkat T细胞中观察到的作用一致，阿维菌素G处理导致粟酒裂殖酵母细胞中泛素化蛋白的过度积累。有趣的是，蛋白酶体缺陷的粟酒裂殖酵母突变体对阿维菌素G的敏感性不明显，而后期促进复合物（有丝分裂泛素连接酶）突变体表现出对阿维菌素G的抗性，这表明阿维菌素G处理导致的泛素化蛋白水平可能升高。由于增加了蛋白质的泛素化作用，而不是抑制了26S蛋白酶体的活性。在cAMP / PKA途径中有缺陷的突变体也表现出对阿维京G的抗性。我们的结果表明，粟酒裂殖酵母将成为阐明阿维京G分子靶标的有用模型生物，并在Rho和/或功能异常的临床应用中提供指导泛素化或泛素化功能已在癌症，纤维化和炎症中得到证实。

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