Polo-like kinase 1 inhibitors, mitotic stress and the tumor suppressor p53

Sanhaji, Mourad; Louwen, Frank; Zimmer, Brigitte; Kreis, Nina-Naomi; Roth, Susanne; Yuan, Juping

doi:10.4161/cc.24573

Cited by 26 publications

(21 citation statements)

References 55 publications

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“…Cell cycle was analyzed as described. 47 siRNA knockdown and MCAK rescue experiments Small interfering RNA (siRNA) (25 nM) targeting the 3 0 -untranslated region of MCAK was synthesized by SigmaAldrich against position 1666 to 1686. siRNA was transiently transfected using the transfection reagent Oligofectamine (Invitrogen, CA) as described. 46,48 For rescue experiments, HeLa cells depleted of endogenous MCAK were transfected with Flagtagged MCAK WT, MCAK S192A or MCAK S192D by using FuGene-HD transfection reagent (Promega, Madisson).…”

Section: Methodsmentioning

confidence: 99%

Functional analysis of phosphorylation of the mitotic centromere-associated kinesin by Aurora B kinase in human tumor cells

et al. 2015

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(2015) Functional analysis of phosphorylation of the mitotic centromere-associated kinesin by Aurora B kinase in human tumor cells, Cell Cycle, 14:23, 3755-3767, DOI: 10.1080/15384101.2015 Keywords: Aurora B, cell motility, MCAK phosphorylation, microtubule dynamics, mitotic defect Abbreviations: ACA, anti-centromere antibody; MCAK, mitotic centromere-associated kinesin; MT, microtubule; MAP, microtubule-associated protein; Plk, Polo-like kinase; Cdk, cyclin-dependent kinase; HUVEC, human umbilical vein endothelial cell; PAK, p21-activated kinase.Mitotic centromere-associated kinesin (MCAK) is the best characterized member of the kinesin-13 family and plays important roles in microtubule dynamics during mitosis. Its activity and subcellular localization is tightly regulated by an orchestra of mitotic kinases, such as Aurora B. It is well known that serine 196 of MCAK is the major phosphorylation site of Aurora B in Xenopus leavis extracts and that this phosphorylation regulates its catalytic activity and subcellular localization. In the current study, we have addressed the conserved phosphorylation site serine 192 in human MCAK to characterize its function in more depth in human cancer cells. Our data confirm that S192 is the major phosphorylation site of Aurora B in human MCAK and that this phosphorylation has crucial roles in regulating its catalytic activity and localization at the kinetochore/centromere region in mitosis. Interfering with this phosphorylation leads to a delayed progression through prometa-and metaphase associated with mitotic defects in chromosome alignment and segregation. We show further that MCAK is involved in directional migration and invasion of tumor cells, and interestingly, interference with the S192 phosphorylation affects this capability of MCAK. These data provide the first molecular explanation for clinical observation, where an overexpression of MCAK was associated with lymphatic invasion and lymph node metastasis in gastric and colorectal cancer patients.

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Section: Methodsmentioning

confidence: 99%

Functional analysis of phosphorylation of the mitotic centromere-associated kinesin by Aurora B kinase in human tumor cells

et al. 2015

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“…33 Briefly, treated cells were trypsinized, washed twice with pre-warmed PBS, fixed and permeabilized with 2% paraformaldehyde and 0.1% Triton X-100 for 15 min at 37 C. Cells were blocked with antibody dilution buffer (10 mM Tris-HCl pH 7.5, 0.9% NaCl, 5 mM EDTA, 1 mg/ml BSA, 10% FCS) for 15 min at 37 C prior to be incubated with mouse monoclonal antibody against pHH3 (S10, Merck Millipore) for 1 h at 37 C, followed by 2 time wash. Cells were then incubated with secondary FITC-labeled polyclonal donkey anti-mouse antibody (DAKO, Hamburg) for 30 min at 37 C. Finally, the stained cells were evaluated with a FACSCalibur (BD Biosciences).…”

Section: Methodsmentioning

confidence: 99%

“…3H). Moreover, the tumor suppressor p53 and the cyclin-dependent kinase inhibitor p21, on which we have worked, [32][33][34][35][36] are multiple functional and greatly impact the cell cycle. Intriguingly, while the gene expression of p21, an important inhibitor of the interphase and functionally also active in mitosis, 35,36 remained nearly unchanged (Fig.…”

Section: Bcl6 Deficiency Induces a Mitotic Arrest Associated With Defmentioning

confidence: 99%

B-cell lymphoma 6 promotes proliferation and survival of trophoblastic cells

et al. 2016

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Preeclampsia is one of the leading causes of maternal and perinatal mortality and morbidity and its pathogenesis is not fully understood. B-cell lymphoma 6 (BCL6), a key regulator of B-lymphocyte development, is altered in preeclamptic placentas. We show here that BCL6 is present in all 3 studied trophoblast cell lines and it is predominantly expressed in trophoblastic HTR-8/SVneo cells derived from a 1 st trimester placenta, suggestive of its involvement in trophoblast expansion in the early stage of placental development. BCL6 is strongly stabilized upon stress stimulation. Inhibition of BCL6, by administrating either small interfering RNA or a specific small molecule inhibitor 79-6, reduces proliferation and induces apoptosis in trophoblastic cells. Intriguingly, depletion of BCL6 in HTR-8/SVneo cells results in a mitotic arrest associated with mitotic defects in centrosome integrity, indicative of its involvement in mitotic progression. Thus, like in haematopoietic cells and breast cancer cells, BCL6 promotes proliferation and facilitates survival of trophoblasts under stress situation. Further studies are required to decipher its molecular roles in differentiation, migration and the fusion process of trophoblasts. Whether increased BCL6 observed in preeclamptic placentas is one of the causes or the consequences of preeclampsia warrants further investigations in vivo and in vitro.

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“…The inhibition of Plk1 uncovers p53-dependent outcomes in response to mitotic stress. In p53-deficient cells, Plk1 inhibitors and microtubule poisons elicit mitotic catastrophe and greater DNA damage than in p53-proficient cells (18). This may reflect the absence of p53-dependent apoptosis that would normally eliminate cells arrested in mitosis.…”

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confidence: 96%

Adenovirus Replaces Mitotic Checkpoint Controls

Turner

Groitl

Dobner

et al. 2015

J Virol

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Infection with adenovirus triggers the cellular DNA damage response, elements of which include cell death and cell cycle arrest. Early adenoviral proteins, including the E1B-55K and E4orf3 proteins, inhibit signaling in response to DNA damage. A fraction of cells infected with an adenovirus mutant unable to express the E1B-55K and E4orf3 genes appeared to arrest in a mitotic-like state. Cells infected early in G 1 of the cell cycle were predisposed to arrest in this state at late times of infection. This arrested state, which displays hallmarks of mitotic catastrophe, was prevented by expression of either the E1B-55K or the E4orf3 genes. However, E1B-55K mutant virus-infected cells became trapped in a mitotic-like state in the presence of the microtubule poison colcemid, suggesting that the two viral proteins restrict entry into mitosis or facilitate exit from mitosis in order to prevent infected cells from arresting in mitosis. The E1B-55K protein appeared to prevent inappropriate entry into mitosis through its interaction with the cellular tumor suppressor protein p53. The E4orf3 protein facilitated exit from mitosis by possibly mislocalizing and functionally inactivating cyclin B1. When expressed in noninfected cells, E4orf3 overcame the mitotic arrest caused by the degradation-resistant R42A cyclin B1 variant. IMPORTANCECells that are infected with adenovirus type 5 early in G 1 of the cell cycle are predisposed to arrest in a mitotic-like state in a p53-dependent manner. The adenoviral E1B-55K protein prevents entry into mitosis. This newly described activity for the E1B-55K protein appears to depend on the interaction between the E1B-55K protein and the tumor suppressor p53. The adenoviral E4orf3 protein facilitates exit from mitosis, possibly by altering the intracellular distribution of cyclin B1. By preventing entry into mitosis and by promoting exit from mitosis, these adenoviral proteins act to prevent the infected cell from arresting in a mitoticlike state.

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Polo-like kinase 1 inhibitors, mitotic stress and the tumor suppressor p53

Cited by 26 publications

References 55 publications

Functional analysis of phosphorylation of the mitotic centromere-associated kinesin by Aurora B kinase in human tumor cells

Functional analysis of phosphorylation of the mitotic centromere-associated kinesin by Aurora B kinase in human tumor cells

B-cell lymphoma 6 promotes proliferation and survival of trophoblastic cells

Adenovirus Replaces Mitotic Checkpoint Controls

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