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Polo样激酶1的长期下调会增加细胞周期蛋白依赖性激酶抑制剂p21(WAF1/CIP1)。

Long-term downregulation of Polo-like kinase 1 increases the cyclin-dependent kinase inhibitor p21(WAF1/CIP1).

作者信息

Kreis Nina-Naomi, Sommer Katharina, Sanhaji Mourad, Krämer Andrea, Matthess Yves, Kaufmann Manfred, Strebhardt Klaus, Yuan Juping

机构信息

Department of Gynecology and Obstetrics, School of Medicine, JW Goethe-University, Frankfurt, Germany.

出版信息

Cell Cycle. 2009 Feb 1;8(3):460-72. doi: 10.4161/cc.8.3.7651. Epub 2009 Feb 18.

Abstract

Polo-like kinase 1 (Plk1) is overexpressed in tumor tissues and its expression level is tightly associated with the malignancy of tumors and prognosis of tumor patients. Thus, Plk1 is considered as one of the most attractive molecular targets for anticancer therapy. Recently, several small molecule inhibitors of Plk1 have been identified and characterized, and the first generation of Plk1 inhibitors has been investigated in clinical trials. However, the long-term effect of the downregulation of Plk1 on tumor cells has not yet been studied. In this work we have investigated the phenotype of HeLa cells, in which Plk1 is continuously downregulated by constitutive expression of shRNA. The data demonstrate that the long-term suppression of Plk1 increases the levels of cyclindependent kinase inhibitor p21(WAF1/CIP), which is partially induced by the elevated tumor suppressor p73 in p53-inactivated HeLa cells. The increased kinase inhibitor p21(WAF1/CIP1) localizes in both cyctoplasm as well as in nucleus and interacts directly with Cdk1/cyclin B1. Moreover, the knockdown of Plk1 leads to a decreased oncoprotein MDM2 and an elevated pro-apoptotic protein Bax in HeLa cells. Importantly, HeLa cells with reduced level of Plk1, which induces an increase of p21, p73 and Bax, are more sensitive to some chemotherapeutic agents, such as cisplatin.

摘要

Polo样激酶1(Plk1)在肿瘤组织中过表达,其表达水平与肿瘤的恶性程度及肿瘤患者的预后密切相关。因此,Plk1被认为是最具吸引力的抗癌治疗分子靶点之一。最近,已鉴定并表征了几种Plk1的小分子抑制剂,第一代Plk1抑制剂已进入临床试验研究阶段。然而,Plk1下调对肿瘤细胞的长期影响尚未得到研究。在本研究中,我们研究了通过组成型表达shRNA持续下调Plk1的HeLa细胞的表型。数据表明,长期抑制Plk1会增加细胞周期蛋白依赖性激酶抑制剂p21(WAF1/CIP)的水平,这在p53失活的HeLa细胞中部分是由肿瘤抑制因子p73升高诱导的。增加的激酶抑制剂p21(WAF1/CIP1)定位于细胞质和细胞核中,并直接与Cdk1/细胞周期蛋白B1相互作用。此外,敲低Plk1会导致HeLa细胞中癌蛋白MDM2减少,促凋亡蛋白Bax增加。重要的是,Plk1水平降低的HeLa细胞,其p21、p73和Bax增加,对某些化疗药物如顺铂更敏感。

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