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Polo-like Kinase (polo-like + kinase)
Selected AbstractsChemInform Abstract: Regioselective Synthesis of Benzimidazole Thiophene Inhibitors of Polo-Like Kinase 1.CHEMINFORM, Issue 7 2009Keith R. Hornberger Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a "Full Text" option. The original article is trackable via the "References" option. [source] Identification and Validation of a Potent Type,II Inhibitor of Inactive Polo-like Kinase,1CHEMMEDCHEM, Issue 11 2009Sarah Keppner Virtual screening using a homology model of human polo-like kinase,1 (Plk1) in an inactive conformation led to the identification of a selective Plk1 inhibitor that decreases proliferation and induces apoptosis. This suggests that type,II Plk1 inhibitors may be considered for the development of cancer therapeutics. [source] Evaluation of malignant and benign gastric biopsy specimens by mRNA expression profile and multivariate statistical methodsCYTOMETRY, Issue 5 2007Orsolya Galamb Abstract Background: mRNA expression array and multivariate statistical analysis of gastric biopsies can yield insight into the molecular biology basis of local alterations, supporting expression-based identification of morphological alterations. Methods: From 11 patients with erosive gastritis(EG), 5 with adenocarcinoma (GC), 11 with atrophic gastritis (AG) gastric biopsies were collected, total RNA isolated, T7 amplification and expression analysis of 1047 mRNAs was performed using commercial glass arrays (Clontech, USA). After microarray quality control, applicable data were available from 7 EG, 4 GC, and 5 AG. Multivariate statistical and cell functional analysis were performed. Real-time RT-PCR and immunohistochemistry were used for validation. Results: GC was characterized by overregulated v-raf, v-erb-a, BCL2-associated- athanogene, immediate-early-response-3, Polo-like kinase, CDK-2, cyclin-C, Pin1 genes, and downregulated ADP-ribosyltransferase, sialophorin and DCC. AG cases had increased PDGF-receptor, TGF-,-receptor-3, and decreased death-associated-protein-3, ,-1-catenin, topoisomerase-1 levels. In EG upregulation of IGF-receptor-1, CD9, transferrin receptor, integrins, and underexpression of keratin-5, caspase-4 was found. Discriminant analysis could reclassify all samples correctly using four parameters. Conclusions: mRNA expression array analysis of gastric biopsies yields previously known and new data in the evaluation of local gastric alterations. © 2007 Clinical Cytometry Society [source] Timing of Plk1 and MPF activation during porcine oocyte maturation,MOLECULAR REPRODUCTION & DEVELOPMENT, Issue 1 2004Martin Anger Abstract A Polo-like kinase 1 (Plk1) appears involved in an autocatalytic loop between CDC25C phosphatase and M phase promoting factor (MPF) in Xenopus oocytes and leads to activation of MPF that is required for germinal vesicle breakdown (GVBD). Although similar evidence for such a role of Plk1 in MPF activation during maturation of mammalian oocytes is absent, changes in Plk1 enzyme activity correlate with MPF activation, Plk1 co-localizes with MPF, and microinjection of antibodies neutralizing Plk1 delays GVBD. In this study, we exploited the prolonged time required for maturation of porcine oocytes to define precisely the timing of Plk1 and MPF activation during maturation. GVBD typically occurs between 24 and 26 hr of culture in vitro and meiotic maturation is completed after 40,44-hr culture. We find that Plk1 is activated before MPF, which is consistent with its role in activating MPF in mammalian oocytes. Mol. Reprod. Dev. 69: 11,16, 2004. © 2004 Wiley-Liss, Inc. [source] Structures of the wild-type and activated catalytic domains of Brachydanio rerio Polo-like kinase 1 (Plk1): changes in the active-site conformation and interactions with ligandsACTA CRYSTALLOGRAPHICA SECTION D, Issue 9 2008Robert A. Elling Polo-like kinase 1 (Plk1) is a member of a family of serine/threonine kinases involved in the regulation of cell-cycle progression and cytokinesis and is an attractive target for the development of anticancer therapeutics. A zebrafish homolog of the human Plk1 (hPlk1) kinase domain (KD) was identified that can be expressed in large quantities in bacteria and crystallizes readily, whether in a wild-type form or as a variant containing the activating Thr196,Asp substitution, in one space group and under similar conditions both in the absence and presence of active-site compounds. This construct was validated by testing a panel of hPlk1 inhibitors against human and zebrafish proteins and it was shown that the selected small molecules inhibited the homologs with a high degree of correlation. Crystal structures of ligand-free wild-type and activated zebrafish Plk1 (zPlk1) KDs revealed the organization of the secondary structural elements around the active site and demonstrated that the activation segment was disordered in the activated form of the domain but possessed a well defined secondary structure in the wild-type enzyme. The cocrystal structure of wild-type zPlk1 KD with ADP documented the hydrolysis of ATP and revealed the phosphorylation site. The cocrystal structure of the activated KD with wortmannin, a covalent inhibitor of Plk1 and PI3 kinases, showed the binding mode of the small molecule to the enzyme and may facilitate the design of more potent Plk1 inhibitors. The work presented in this study establishes the zPlk1 KD as a useful tool for rapid low- and high-throughput structure-based screening and drug discovery of compounds specific for this mitotic target. [source] Regulatory mechanisms and functions of intermediate filaments: A study using site- and phosphorylation state-specific antibodiesCANCER SCIENCE, Issue 3 2006Ichiro Izawa Intermediate filaments (IF) form the structural framework of the cytoskeleton. Although histopathological detection of IF proteins is utilized for examining cancer specimens as reliable markers, the molecular mechanisms by which IF are involved in the biology of cancer cells are still unclear. We found that site-specific phosphorylation of IF proteins induces the disassembly of filament structures. To further dissect the in vivo spatiotemporal dynamics of IF phosphorylation, we developed site- and phosphorylation state-specific antibodies. Using these antibodies, we detected kinase activities that specifically phosphorylate type III IF, including vimentin, glial fibrillary acidic protein and desmin, during mitosis. Cdk1 phosphorylates vimentin-Ser55 from prometaphase to metaphase, leading to the recruitment of Polo-like kinase 1 (Plk1) to vimentin. Upon binding to Phospho-Ser55 of vimentin, Plk1 is activated, and then phosphorylates vimentin-Ser82. During cytokinesis, Rho-kinase and Aurora-B specifically phosphorylate IF at the cleavage furrow. IF phosphorylation by Cdk1, Plk1, Rho-kinase and Aurora-B plays an important role in the local IF breakdown, and is essential for the efficient segregation of IF networks into daughter cells. As another part of our research on IF, we have set out to find the binding partners with simple epithelial keratin 8/18. We identified tumor necrosis factor receptor type 1-associated death domain protein (TRADD) as a keratin 18-binding protein. Together with data from other laboratories, it is proposed that simple epithelial keratins may play a role in modulating the response to some apoptotic signals. Elucidation of the precise molecular functions of IF is expected to improve our understanding of tumor development, invasion and metastasis. (Cancer Sci 2006; 97: 167,174) [source] Overexpression of cyclooxygenase-2 in human prostate carcinoma and prostatic intraepithelial neoplasia-association with increased expression of polo-like kinase-1THE PROSTATE, Issue 4 2007Carsten Denkert Abstract BACKGROUND Cyclooxygenases (COX) as well as Polo-like kinases (PLK) are involved in proliferation and cell cycle regulation and have been suggested for preventive and therapeutic approaches in prostate carcinoma. METHODS In this study, we studied expression and prognostic impact of COX-2 in invasive prostate carcinoma, prostatic intraepithelial neoplasia (PIN), atrophic glands, and normal prostatic glands, and investigated the association between COX-2 and PLK-1. RESULTS We observed a positivity for COX-2 in 72.1% of PIN and in 44.7% of prostate carcinomas with an overexpression of COX-2 in prostate cancer and PIN compared to benign prostatic tissue (P,<,0.0005). Furthermore, we observed a strong correlation between expression of PLK-1 and COX-2 (P,<,0.0005). CONCLUSIONS To our knowledge, this is the first report of a correlation between COX-2 and PLK-1 in a malignant tumor. COX-2 and PLK-1 may be interesting targets for new molecular therapies in prostate cancer. Prostate 67: 361,369, 2007. © 2007 Wiley-Liss, Inc. [source] Identification and Validation of a Potent Type,II Inhibitor of Inactive Polo-like Kinase,1CHEMMEDCHEM, Issue 11 2009Sarah Keppner Virtual screening using a homology model of human polo-like kinase,1 (Plk1) in an inactive conformation led to the identification of a selective Plk1 inhibitor that decreases proliferation and induces apoptosis. This suggests that type,II Plk1 inhibitors may be considered for the development of cancer therapeutics. [source] | ||||||||||||||||