P190B RhoGAP Regulates Chromosome Segregation in Cancer Cells.
P190B RhoGAP Regulates Chromosome Segregation in Cancer Cells.
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DOI：
10.3390/cancers4020475
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发表时间：
2012-06-01
期刊：
影响因子：
5.2
通讯作者：
Vargo-Gogola, Tracy
中科院分区：
文献类型：
--
作者：
Hwang, Melissa;Peddibhotla, Sirisha;Vargo-Gogola, Tracy
Rho GTP酶在包括乳腺癌在内的许多癌症中过表达和过度活化。Rho蛋白及其调节因子和效应因子与有丝分裂有关，它们的表达改变促进有丝分裂缺陷和非整倍性。以前，我们证明了p190 B Rho GT3激活蛋白（RhoGAP）缺陷抑制ErbB 2诱导的小鼠乳腺肿瘤形成。在这里，我们描述了一个新的作用p190 B作为有丝分裂的调节器。我们发现，p190 B定位于中心体在间期和有丝分裂，并在有丝分裂过程中差异磷酸化。MCF-7和Hela细胞中p190 B表达的敲低增加了中期异常微管-动粒附着、后期落后染色体和微核的发生率，所有这些都是非整倍体的指示。p190 B缺陷MCF-7细胞的细胞周期分析显示凋亡细胞显著增加，同时G1和S期细胞减少，表明p190 B缺陷细胞在G1至S期转变时死亡。在有丝分裂过程中，化学抑制Rac GTdR使p190 B敲低细胞中落后染色体的发生率降低至对照细胞中检测到的水平，表明在p190 B不存在的情况下，Rac活性异常促进染色体分离缺陷。总之，这些数据表明，p190 B调节癌细胞中的染色体分离和凋亡。我们认为有丝分裂的中断可能是p190 B缺陷抑制肿瘤发生的机制之一。
Rho GTPases are overexpressed and hyperactivated in many cancers, including breast cancer. Rho proteins, as well as their regulators and effectors, have been implicated in mitosis, and their altered expression promotes mitotic defects and aneuploidy. Previously, we demonstrated that p190B Rho GTPase activating protein (RhoGAP) deficiency inhibits ErbB2-induced mammary tumor formation in mice. Here we describe a novel role for p190B as a regulator of mitosis. We found that p190B localized to centrosomes during interphase and mitosis, and that it is differentially phosphorylated during mitosis. Knockdown of p190B expression in MCF-7 and Hela cells increased the incidence of aberrant microtubule-kinetochore attachments at metaphase, lagging chromosomes at anaphase, and micronucleation, all of which are indicative of aneuploidy. Cell cycle analysis of p190B deficient MCF-7 cells revealed a significant increase in apoptotic cells with a concomitant decrease in cells in G1 and S phase, suggesting that p190B deficient cells die at the G1 to S transition. Chemical inhibition of the Rac GTPase during mitosis reduced the incidence of lagging chromosomes in p190B knockdown cells to levels detected in control cells, suggesting that aberrant Rac activity in the absence of p190B promotes chromosome segregation defects. Taken together, these data suggest that p190B regulates chromosome segregation and apoptosis in cancer cells. We propose that disruption of mitosis may be one mechanism by which p190B deficiency inhibits tumorigenesis.