Journal ArticleDOI
Polo-like kinase-1 is activated by aurora A to promote checkpoint recovery
Libor Macůrek,Arne Lindqvist,Daniel Lim,Michael A. Lampson,Rob Klompmaker,Raimundo Freire,Christophe Clouin,Stephen S. Taylor,Michael B. Yaffe,René H. Medema +9 more
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TLDR
It is demonstrated that the initial activation of PLK1 is a primary function of aurora A, and that Bora/aurora-A-dependent phosphorylation is a prerequisite for PLK 1 to promote mitotic entry after a checkpoint-dependent arrest.Abstract:
Polo-like kinase-1 (PLK1) is an essential mitotic kinase regulating multiple aspects of the cell division process. Activation of PLK1 requires phosphorylation of a conserved threonine residue (Thr 210) in the T-loop of the PLK1 kinase domain, but the kinase responsible for this has not yet been affirmatively identified. Here we show that in human cells PLK1 activation occurs several hours before entry into mitosis, and requires aurora A (AURKA, also known as STK6)-dependent phosphorylation of Thr 210. We find that aurora A can directly phosphorylate PLK1 on Thr 210, and that activity of aurora A towards PLK1 is greatly enhanced by Bora (also known as C13orf34 and FLJ22624), a known cofactor for aurora A (ref. 7). We show that Bora/aurora-A-dependent phosphorylation is a prerequisite for PLK1 to promote mitotic entry after a checkpoint-dependent arrest. Importantly, expression of a PLK1-T210D phospho-mimicking mutant partially overcomes the requirement for aurora A in checkpoint recovery. Taken together, these data demonstrate that the initial activation of PLK1 is a primary function of aurora A.read more
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Cell Cycle Proteins as Promising Targets in Cancer Therapy
Tobias Otto,Piotr Sicinski +1 more
TL;DR: The role of cell cycle proteins in cancer, the rationale for targeting them in cancer treatment and results of clinical trials, as well as the future therapeutic potential of various cell cycle inhibitors are discussed.
Journal ArticleDOI
A Genome-wide RNAi Screen Identifies Multiple Synthetic Lethal Interactions with the Ras Oncogene
Ji Luo,Michael J. Emanuele,Danan Li,Chad J. Creighton,Michael R. Schlabach,Thomas F. Westbrook,Kwok-Kin Wong,Stephen J. Elledge +7 more
TL;DR: A pathway involving the mitotic kinase PLK1, the anaphase-promoting complex/cyclosome, and the proteasome that, when inhibited, results in prometaphase accumulation and the subsequent death of Ras mutant cells is described.
Journal ArticleDOI
The Chromosomal Instability Pathway in Colon Cancer
Maria Pino,Daniel C. Chung +1 more
TL;DR: An updated perspective is provided on the mechanisms that lead to CIN and the key mutations that are acquired in this pathway, which is characterized by widespread imbalances in chromosome number and loss of heterozygosity.
Journal ArticleDOI
Multifaceted polo-like kinases: drug targets and antitargets for cancer therapy
TL;DR: Recent insights into the biology of PLKs will be reviewed, with an emphasis on their role in malignant transformation, and progress in the development of small-molecule PLK1 inhibitors will be examined.
Journal ArticleDOI
Shared and separate functions of polo-like kinases and aurora kinases in cancer
TL;DR: It is becoming clear that interplay between polo-like kinases and aurora kinases is much more extensive than initially anticipated, and that both kinase families are important factors in the response to classical chemotherapeutics that damage the genome or the mitotic spindle.
References
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Journal ArticleDOI
A System for Stable Expression of Short Interfering RNAs in Mammalian Cells
TL;DR: It is shown that siRNA expression mediated by this vector causes efficient and specific down-regulation of gene expression, resulting in functional inactivation of the targeted genes.
Journal ArticleDOI
BI 2536, a Potent and Selective Inhibitor of Polo-like Kinase 1, Inhibits Tumor Growth In Vivo
Martin Steegmaier,Matthias Hoffmann,Anke Baum,Péter Lénárt,Mark Petronczki,Martin Krššák,Ulrich Gürtler,Pilar Garin-Chesa,Simone Lieb,Jens Quant,Matthias Grauert,Günther R. Adolf,Norbert Kraut,Jan-Michael Peters,Wolfgang J. Rettig +14 more
TL;DR: A potent small-molecule inhibitor of mammalian Plk1, BI 2536, is reported, which inhibits PlK1 enzyme activity at low nanomolar concentrations and causes a mitotic arrest and induces apoptosis in human cancer cell lines of diverse tissue origin and oncogenome signature.
Journal ArticleDOI
The Small-Molecule Inhibitor BI 2536 Reveals Novel Insights into Mitotic Roles of Polo-like Kinase 1
Péter Lénárt,Mark Petronczki,Martin Steegmaier,Barbara Di Fiore,Jesse J. Lipp,Matthias Hoffmann,Wolfgang J. Rettig,Norbert Kraut,Jan-Michael Peters +8 more
TL;DR: The results suggest that Plk1's accumulation at centrosomes and Kinetochores depends on its own activity and that this activity is required for maintaining centrosome and kinetochore function.
Journal ArticleDOI
A genetically encoded fluorescent reporter reveals oscillatory phosphorylation by protein kinase C
TL;DR: Novel FRET-based reporters for PKC translocation, phosphoinositide bisphosphate conversion to IP3, and diacylglycerol show that in HeLa cells the oscillatory phosphorylations correlate with Ca2+-controlled translocation of conventional PKC to the membrane without oscillations of PLC activity or diacyg Glycerol.
Journal ArticleDOI
Polo-like kinase-1 is a target of the DNA damage checkpoint.
Veronique A. J. Smits,Rob Klompmaker,Lionel Arnaud,Lionel Arnaud,Gert Rijksen,Erich A. Nigg,Erich A. Nigg,René H. Medema +7 more
TL;DR: It is proposed that Plk1 is an important target of the DNA damage checkpoint, enabling cell-cycle arrests at multiple points in G2 and mitosis, and blocking mitotic exit.