英语翻译文章长,可以给发过去,帮我翻译这一部分也好.图片接下文,周三要交.Polo-like kinase 1 (Plk1) is an important target for antineoplastic therapy because of its required functions in cell division,as well as the enhance

英语翻译文章长,可以给发过去,帮我翻译这一部分也好.图片接下文,周三要交.Polo-like kinase 1 (Plk1) is an important target for antineoplastic therapy because of its required functions in cell division,as well as the enhance
英语翻译
文章长,可以给发过去,帮我翻译这一部分也好.图片接下文,周三要交.
Polo-like kinase 1 (Plk1) is an important target for antineoplastic therapy because of its required functions in cell division,as well as the enhanced sensitivity of cancer cells to its inactivation.Several Plk1-targeted drugs have emerged,including BI-2536 and ZK-thiazolidinone (TAL).These inhibitors of Plk1 arrest cells in mitosis and evoke phenotypes consistent with downregulating Plk1 by other means.BI-2536 and a pharmacologically optimized analogue (BI-6727) have shown promising signs of activity in preliminary clinical trials.A chemical genetic system for inhibiting Plk1 has also been developed.In this system,both copies of the PLK1 locus were deleted from immortalized human retinal pigment epithelial cells through targeting and Cre-lox-mediated recombination.After Cre-mediated excision,PLK1–/– clones are inviable unless they are complemented by expression of Plk1 in trans,either wildtype (Plk1wt) or a compound mutant (L130G C67V; hereafter Plk1as).By enlarging the kinase’s active site,the latter mutations allow Plk1 to accept bulky purine analogues as ATP-competitive inhibitors.We report here that these mutations also have the unexpected effect of desensitizing Plk1 to clinically useful inhibitors such as BI-2536 and TAL.(Structures for all chemicals used are shown in Supplementary Figure 1.)
In the course of examining the anti-proliferative activity of BI-2536,we discovered that this compound strongly retarded the growth of Plk1wt cells but had little or no effect on Plk1as cells (Figure 1A,B).To determine if this change in inhibitor potency was unique to BI-2536,we performed similar growth-challenge experiments with TAL,a structurally distinct Plk1 inhibitor.Again,we observed a marked difference between Plk1as cells and their isogenic Plk1wt counterparts (Figure 1C,D).To understand the depth and breadth of inhibitor resistance,we queried multiple in vivo readouts of Plk1 activity.Plk1 is required throughout mitosis,with well-characterized roles in centrosome maturation,bipolar spindle assembly,stabilization of kinetochore-microtubule attachments,and initiation of cytokinesis.Each of these programs proved to be qualitatively and quantitatively resistant to both Plk1-targeted inhibitors.For instance,Plk1as cells continued to recruit γ-tubulin to centrosomes (a cardinal manifestation of centrosome maturation) and form bipolar spindles in the presence of BI-2536 (Figure 2A) and TAL (Figure 2B).Likewise,BubR1 hyper-phosphorylation by Plk1 (a crucial determinant of stable kinetochore-microtubule attachment) was undiminished,as reflected in the BubR1 polypeptide’s persistent mobility shift on SDS-PAGE (Figure 2C).Consistent with this broad array of defects,both compounds caused Plk1wt (but not Plk1as cells) to arrest in mitosis,as judged from their rounded appearance by phase-contrast microscopy (shown below in Figure 4).

英语翻译文章长,可以给发过去,帮我翻译这一部分也好.图片接下文,周三要交.Polo-like kinase 1 (Plk1) is an important target for antineoplastic therapy because of its required functions in cell division,as well as the enhance
马可波罗样激酶1（PLK 1）是一个重要的目标,抗癌疗法由于其所需的功能在细胞分裂,以及提高灵敏度癌细胞失活.几plk1-targeted药物已经出现,包括bi-2536和zk-thiazolidinone（鲎）.这些抑制剂及逮捕细胞有丝分裂和表型符合下调Plk 1的其他means.bi-2536和药理优化模拟（bi-6727）已表明希望的活动迹象的初步临床试验.化学基因系统抑制能力也得到了发展.在这个系统中,两个拷贝的PLK 1基因被删除的永生化人视网膜色素上皮细胞通过定位和cre-lox-mediated重组.在酶Cre介导的切除,PLK 1–/–克隆无法除非他们补充表达Plk 1反,要么野生型（plk1wt）或复合突变（l130g c67v；此后plk1as）.通过扩大激酶的活性位点,后者突变允许Plk 1接受笨重的嘌呤类似物如三磷酸腺苷竞争抑制剂.我们在这里报告,这些突变也有意外影响脱敏Plk 1临床有用的抑制剂如bi-2536和塔尔.（结构使用的所有化学品都显示在补充图1.）
检查中抗增殖活性的bi-2536,我们发现,这种化合物强烈迟钝增长plk1wt细胞,但很少或根本没有影响plk1as细胞（图1,2）.要确定是否改变抑制剂效力是独一无二的bi-2536,我们进行类似的growth-challenge实验环境,结构不同的Plk 1抑制剂.再次,我们观察到显着差异plk1as细胞和基因plk1wt同行（数字集成电路,开发）.理解的深度和广度抑制剂抵抗,我们询问体内多种读数及活动.PLK 1需要在整个有丝分裂,良好的作用,中心体成熟,双极纺锤体组装,稳定的动粒微管的附件,并开始胞质.所有这些程序证明是定性和定量抗两种plk1-targeted抑制剂.例如,plk1as细胞继续招募γ-微管蛋白的中心体（一种基本表现中心体成熟）和形式双极纱锭中存在的bi-2536（图2）和塔尔（图乙）.同样,hyper-phosphorylation BubR 1能力（一个关键因素,稳定的动粒微管附件）是不受减损,体现在如BubR 1多肽的持续流动转移电泳（图2）.符合这一广泛的缺陷,这两种化合物造成plk1wt（但不plk1as细胞）逮捕的有丝分裂,看他们的圆形外观相差显微镜（如图4所示）.