Switching Polo-like kinase-1 on and off in time and space

Bruinsma, Wytse; Raaijmakers, Jonne A.; Medema, René H.

doi:10.1016/j.tibs.2012.09.005

Cited by 112 publications

(118 citation statements)

References 85 publications

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“…Its deregulation has been shown to increase genomic instability, favoring cancer maintenance 15 ; however, the heterogeneity and prevalence in its expression is directly associated with the proliferation rate of the cell. 16 High levels of PLK1 have been described in different tumor cells, including GBM, 17 and its expression level has even been correlated with prognosis.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Polo-Like Kinase 1 Induces Cell Cycle Arrest and Sensitizes Glioblastoma Cells to Ionizing Radiation

Pezuk

Brassesco

Morales

et al. 2013

Cancer Biotherapy and Radiopharmaceuticals

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Despite efforts to improve surgical, radiologic, and chemotherapeutic strategies, the outcome of patients with glioblastoma (GBM) is still poor. Polo-like kinase 1 (PLK1) is a serine/threonine kinase that plays key roles in cell cycle control and has been associated with tumor growth and prognosis. Here, we aimed at testing the radiosensitizing effects of the PLK1 inhibitor BI 2536 on eight GBM cell lines. For cell cycle analysis, T98G, U251, U343 MG-a, LN319, SF188, U138 MG, and U87 MG cell lines were treated with 10, 50, or 100 nM of BI 2536 for 24 hours. In addition, cell cultures exposed to BI 2536 50 nM for 24 hours were irradiated with c-rays from 60 Cobalt source at final doses of 2, 4, and 6 Gy. Combinatorial effects were evaluated through proliferation and clonogenic capacity assays. Treatment with BI 2536 caused mitotic arrest after 24 hours, and increased apoptosis in GBM cells. Moreover, our results demonstrate that pretreatment with this drug sensitized six out of seven GBM cell lines to different doses of c-irradiation as shown by decreased growth and abrogation of colony-formation capacity. Our data suggest that PLK1 blockage has a radiosensitizing effect on GBM, which could improve treatment strategies for this devastating tumor.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Polo-Like Kinase 1 Induces Cell Cycle Arrest and Sensitizes Glioblastoma Cells to Ionizing Radiation

Pezuk

Brassesco

Morales

et al. 2013

Cancer Biotherapy and Radiopharmaceuticals

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“…30,31 In addition, Plk1 is required for recovery from the G2 checkpoint. 32,33 This is achieved by induction of the bTrCP-dependent degradation of Claspin, a cofactor of ATR required for activation of Chk1 and for establishing the checkpoint.…”

Section: Plk1 Phosphorylates 53bp1 During Mitosis At Ser1618 In the Umentioning

confidence: 99%

Polo-like kinase 1 inhibits DNA damage response during mitosis

et al. 2015

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Abbreviations: 53BP1, p53 binding protein 1; ATM, ataxia telangiectasia mutated kinase; BRCA1, breast cancer type 1 susceptibility protein; Cdk, cyclin dependent kinase; DDR, DNA damage response; Plk1, Polo-like kinase 1; H2AX, histone variant H2AX; IR -ionizing radiation; MDC1, mediator of DNA damage checkpoint protein 1; NCS -neocarzinostatin; NZ -nocodazole; PTIP, PAX transactivation activation domain-interacting protein; RIF1, Rap1-interacting factor 1 homolog; RNAi, RNA interference; RNF8, RING finger protein 8; RNF168, RING finger protein 168.In response to genotoxic stress, cells protect their genome integrity by activation of a conserved DNA damage response (DDR) pathway that coordinates DNA repair and progression through the cell cycle. Extensive modification of the chromatin flanking the DNA lesion by ATM kinase and RNF8/RNF168 ubiquitin ligases enables recruitment of various repair factors. Among them BRCA1 and 53BP1 are required for homologous recombination and nonhomologous end joining, respectively. Whereas mechanisms of DDR are relatively well understood in interphase cells, comparatively less is known about organization of DDR during mitosis. Although ATM can be activated in mitotic cells, 53BP1 is not recruited to the chromatin until cells exit mitosis. Here we report mitotic phosphorylation of 53BP1 by Plk1 and Cdk1 that impairs the ability of 53BP1 to bind the ubiquitinated H2A and to properly localize to the sites of DNA damage. Phosphorylation of 53BP1 at S1618 occurs at kinetochores and in cytosol and is restricted to mitotic cells. Interaction between 53BP1 and Plk1 depends on the activity of Cdk1. We propose that activity of Cdk1 and Plk1 allows spatiotemporally controlled suppression of 53BP1 function during mitosis.

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“…Plks are highly expressed in proliferating cells and are overexpressed in a variety of cancers where they have the potential to promote chromosomal instability and tumorigenesis (5)(6)(7)(8)(9). Previous studies have shown that Plk kinase activity can be limited to brief periods within the cell cycle through mechanisms involving the transcription, localization, degradation, and autoinhibition of the kinase (3,(10)(11)(12)(13). New regulatory mechanisms of Plks continue to be identified (14)(15)(16), making it clear that our understanding of Plk regulation is incomplete.…”

mentioning

confidence: 99%

“…PBs are ∼100-aa multifunctional domains that serve as hubs of protein interaction and are important for dimerization, substrate binding, intracellular targeting, and autoinhibition of kinase activity (3,4,12,13,17). Plk1-3 contain two PBs, whereas Plk4 contains three distinct PBs (18).…”

mentioning

confidence: 99%

Autoinhibition and relief mechanism for Polo-like kinase 4

Klebba

Buster

McLamarrah

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Polo-like kinase 4 (Plk4) is a master regulator of centriole duplication, and its hyperactivity induces centriole amplification. Homodimeric Plk4 has been shown to be ubiquitinated as a result of autophosphorylation, thus promoting its own degradation and preventing centriole amplification. Unlike other Plks, Plk4 contains three rather than two Polo box domains, and the function of its third Polo box (PB3) is unclear. Here, we performed a functional analysis of Plk4's structural domains. Like other Plks, Plk4 possesses a previously unidentified autoinhibitory mechanism mediated by a linker (L1) near the kinase domain. Thus, autoinhibition is a conserved feature of Plks. In the case of Plk4, autoinhibition is relieved after homodimerization and is accomplished by PB3 and by autophosphorylation of L1. In contrast, autophosphorylation of the second linker promotes separation of the Plk4 homodimer. Therefore, autoinhibition delays the multiple consequences of activation until Plk4 dimerizes. These findings reveal a complex mechanism of Plk4 regulation and activation which govern the process of centriole duplication.autoinhibition | centriole | centrosome | Polo box | Polo-like kinase 4

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Switching Polo-like kinase-1 on and off in time and space

Cited by 112 publications

References 85 publications

Inhibition of Polo-Like Kinase 1 Induces Cell Cycle Arrest and Sensitizes Glioblastoma Cells to Ionizing Radiation

Inhibition of Polo-Like Kinase 1 Induces Cell Cycle Arrest and Sensitizes Glioblastoma Cells to Ionizing Radiation

Polo-like kinase 1 inhibits DNA damage response during mitosis

Autoinhibition and relief mechanism for Polo-like kinase 4

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