title: Long-term downregulation of Polo-like kinase 1 increases the cyclin-dependent kinase inhibitor p21(WAF1/CIP1).
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.
authors.affiliation: Department of Gynecology and Obstetrics, School of Medicine, JW Goethe-University, Frankfurt, Germany.
authors.forename: Nina-Naomi
authors.initials: NN
authors.lastname: Kreis
authors.forename: Katharina
authors.initials: K
authors.lastname: Sommer
authors.forename: Mourad
authors.initials: M
authors.lastname: Sanhaji
authors.forename: Andrea
authors.initials: A
authors.lastname: Krämer
authors.forename: Yves
authors.initials: Y
authors.lastname: Matthess
authors.forename: Manfred
authors.initials: M
authors.lastname: Kaufmann
authors.forename: Klaus
authors.initials: K
authors.lastname: Strebhardt
authors.forename: Juping
authors.initials: J
authors.lastname: Yuan
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000502:physiology; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D002869:Chromosome Aberrations; D002875:Chromosomes / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D008941:Spindle Apparatus / Q000378:metabolism / Q000473:pathology; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D051028:bcl-2-Associated X Protein; D000097869:Polo-Like Kinase 1; C000606460:TP73 protein, human