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蛋白酶体抑制剂可诱导人胶质瘤细胞发生不依赖p53/p21的凋亡。

Proteasome inhibitors induce p53/p21-independent apoptosis in human glioma cells.

作者信息

Wagenknecht B, Hermisson M, Eitel K, Weller M

机构信息

Laboratory of Molecular Neuro-Oncology, Department of Neurology, University of Tübingen, School of Medicine, Tübingen, Germany.

出版信息

Cell Physiol Biochem. 1999;9(3):117-25. doi: 10.1159/000016308.

Abstract

The proteasome is a multiprotein complex involved in the degradation of ubiquitinated proteins. Three proteasome inhibitors, calpain inhibitor I, lactacystin and MG132, induced apoptosis in several human malignant glioma cell lines. Although proteasome inhibitors induced p53 accumulation in a cell line retaining wild-type p53 activity, p53 activity was dispensable for apoptosis since transdominant-negative p53 abrogated p53-dependent p21 induction but did not modulate apoptosis. Further, p21 was induced by higher concentrations of proteasome inhibitors in a p53-independent manner both in p53 wild-type and in p53 mutant cell lines. Although there was a strong G2/M arrest in response to proteasome inhibition in glioma cells, this G2/M arrest was also observed in p21(-/-) colon carcinoma cells, suggesting that p21 is dispensable for the G2/M arrest associated with proteasome inhibition. Interestingly, the p21(-/-) cells were more resistant to protease inhibitors than parental p21(+/+) cells. In summary, our data indicate that proteasome inhibition induces a p21-independent G2/M arrest and p53-independent apoptosis in human malignant glioma cells.

摘要

蛋白酶体是一种参与泛素化蛋白降解的多蛋白复合物。三种蛋白酶体抑制剂,即钙蛋白酶抑制剂I、乳胞素和MG132,可在多种人类恶性胶质瘤细胞系中诱导细胞凋亡。尽管蛋白酶体抑制剂在保留野生型p53活性的细胞系中诱导p53积累,但由于显性负性p53消除了p53依赖性的p21诱导作用但未调节细胞凋亡,因此p53活性对于细胞凋亡是可有可无的。此外,在p53野生型和p53突变细胞系中,较高浓度的蛋白酶体抑制剂均以p53非依赖性方式诱导p21表达。尽管胶质瘤细胞在蛋白酶体抑制作用下出现强烈的G2/M期阻滞,但在p21(-/-)结肠癌细胞中也观察到这种G2/M期阻滞,这表明p21对于与蛋白酶体抑制相关的G2/M期阻滞是可有可无的。有趣的是,p21(-/-)细胞比亲本p21(+/+)细胞对蛋白酶抑制剂更具抗性。总之,我们的数据表明,蛋白酶体抑制在人类恶性胶质瘤细胞中诱导p21非依赖性的G2/M期阻滞和p53非依赖性的细胞凋亡。

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