Use of the novel Plk1 inhibitor ZK-thiazolidinone to elucidate functions of Plk1 in early and late stages of mitosis.
Polo-like kinase 1 (Plk1) is a key regulator of mitotic progression and cell division in eukaryotes. It is highly expressed in tumor cells and considered a potential target for cancer therapy. Here, we report the discovery and application of a novel potent small-molecule inhibitor of mammalian Plk1, ZK-Thiazolidinone (TAL). We have extensively characterized TAL in vitro and addressed TAL specificity within cells by studying Plk1 functions in sister chromatid separation, centrosome maturation, and spindle assembly. Moreover, we have used TAL for a detailed analysis of Plk1 in relation to PICH and PRC1, two prominent interaction partners implicated in spindle assembly checkpoint function and cytokinesis, respectively. Specifically, we show that Plk1, when inactivated by TAL, spreads over the arms of chromosomes, resembling the localization of its binding partner PICH, and that both proteins are mutually dependent on each other for correct localization. Finally, we show that Plk1 activity is essential for cleavage furrow formation and ingression, leading to successful cytokinesis.
Santamaria
Anna
A
Department of Cell Biology and Intracellular Protein Transport, Independent Junior Research Group, Max-Planck Institute of Biochemistry, Martinsried, 82152 Germany.
Neef
Rüdiger
R
Eberspächer
Uwe
U
Eis
Knut
K
Husemann
Manfred
M
Mumberg
Dominik
D
Prechtl
Stefan
S
Schulze
Volker
V
Siemeister
Gerhard
G
Wortmann
Lars
L
Barr
Francis A
FA
Nigg
Erich A
EA
D000705:Anaphase / Q000187:drug effects; D000814:Aniline Compounds / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D045744:Cell Line, Tumor; D018385:Centrosome / Q000187:drug effects / Q000201:enzymology; D002842:Chromatids / Q000187:drug effects / Q000201:enzymology; D048749:Cytokinesis / Q000187:drug effects; D004265:DNA Helicases; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D051379:Mice; D008938:Mitosis / Q000187:drug effects*; D008940:Mitotic Index; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D008941:Spindle Apparatus / Q000187:drug effects / Q000201:enzymology; D053778:Thiazolidines / Q000737:chemistry / Q000494:pharmacology*; D000097869:Polo-Like Kinase 1
D000814:Aniline Compounds; D018797:Cell Cycle Proteins; D004265:DNA Helicases; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D053778:Thiazolidines; D000097869:Polo-Like Kinase 1; C524394:ZK-thiazolidinone; C516980:ERCC6L protein, human