Polo-like kinase-1 in DNA damage response

Hyun, Sun Yi; Hwan, Hyo In; Jang, Young Joo

doi:10.5483/bmbrep.2014.47.5.061

Cited by 53 publications

(49 citation statements)

References 84 publications

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“…‘G2/M cell cycle checkpoint regulation’, ‘p53 signaling’, ‘GADD signaling’ or ‘Polo-like kinase signaling’ can be associated with DNA damage and stress reactions in response to a chronic exposure to tobacco fumes or other volatile carcinogens [25, 27, 34–36]. The observed activations of ‘ERK/MAPK Signaling’ (z-score: 2.236) or ‘PI3K/AKT Signaling’ (z-score: 2.449) are common in many different cancers and may gradually enhance survival and proliferation of preinvasive and invasive cells in the included samples [28].…”

Section: Discussionmentioning

confidence: 99%

Whole Transcriptome Analysis of Pre-invasive and Invasive Early Squamous Lung Carcinoma in Archival Laser Microdissected Samples

Koper

Zeef

Joseph³

et al. 2017

Respir Res

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BackgroundPreinvasive squamous cell cancer (PSCC) are local transformations of bronchial epithelia that are frequently observed in current or former smokers. Their different grades and sizes suggest a continuum of dysplastic change with increasing severity, which may culminate in invasive squamous cell carcinoma (ISCC). As a consequence of the difficulty in isolating cancerous cells from biopsies, the molecular pathology that underlies their histological variability remains largely unknown.MethodTo address this issue, we have employed microdissection to isolate normal bronchial epithelia and cancerous cells from low- and high-grade PSCC and ISCC, from paraffin embedded (FFPE) biopsies and determined gene expression using Affymetric Human Exon 1.0 ST arrays. Tests for differential gene expression were performed using the Bioconductor package limma followed by functional analyses of differentially expressed genes in IPA.ResultsExamination of differential gene expression showed small differences between low- and high-grade PSCC but substantial changes between PSCC and ISCC samples (184 vs 1200 p-value <0.05, fc ±1.75). However, the majority of the differentially expressed PSCC genes (142 genes: 77%) were shared with those in ISCC samples. Pathway analysis showed that these shared genes are associated with DNA damage response, DNA/RNA metabolism and inflammation as major biological themes. Cluster analysis identified 12 distinct patterns of gene expression including progressive up or down-regulation across PSCC and ISCC. Pathway analysis of incrementally up-regulated genes revealed again significant enrichment of terms related to DNA damage response, DNA/RNA metabolism, inflammation, survival and proliferation. Altered expression of selected genes was confirmed using RT-PCR, as well as immunohistochemistry in an independent set of 45 ISCCs.ConclusionsGene expression profiles in PSCC and ISCC differ greatly in terms of numbers of genes with altered transcriptional activity. However, altered gene expression in PSCC affects canonical pathways and cellular and biological processes, such as inflammation and DNA damage response, which are highly consistent with hallmarks of cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-016-0496-3) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Whole Transcriptome Analysis of Pre-invasive and Invasive Early Squamous Lung Carcinoma in Archival Laser Microdissected Samples

Koper

Zeef

Joseph³

et al. 2017

Respir Res

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“…13 In light of the interphase roles of PLK1, 42 it is particularly interesting that upregulated interactors identified for the mutant Jade-1S S18/20A included TOPORS, which, like the Jade1S interacting partner Kat7/HBO1, is associated with recognition of genotoxic stress 15,46 and regulated by PLK1. 47,48 Given a requirement for PLK1 in cell cycle progression especially after DNA damage, 49,50 and the links between tissue repair and Jade1S described above, a relationship between Jade-1S and PLK1 during the cell cycle is intriguing. Mechanisms underlying S-phase delay could involve impaired regulation of the Jade1/HBO1 histone acetylation complex, and may directly involve PLK1 as PLK1-mediated phosphorylation of HBO1 contributes to pre-replicative complex formation and DNA replication licensing.…”

Section: Discussionmentioning

confidence: 99%

Jade-1S phosphorylation induced by CK1α contributes to cell cycle progression

et al. 2016

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The PHD zinc finger protein Jade-1S is a component of the HBO1 histone acetyltransferase complex and binds chromatin in a cell cycle-dependent manner. Jade-1S also acts as an E3 ubiquitin ligase for the canonical Wnt effector protein b-catenin and is influenced by CK1a-mediated phosphorylation. To further elucidate the functional impact of this phosphorylation, we used a stable, low-level expression system to express either wild-type or mutant Jade-1S lacking the N-terminal CK1a phosphorylation motif. Interactome analyses revealed that the Jade-1S mutant unable to be phosphorylated by CK1a has an increased binding affinity to proteins involved in chromatin remodelling, histone deacetylation, transcriptional repression, and ribosome biogenesis. Interestingly, cells expressing the mutant displayed an elongated cell shape and a delay in cell cycle progression. Finally, phosphoproteomic analyses allowed identification of a Jade-1S site phosphorylated in the presence of CK1a but closely resembling a PLK1 phosphorylation motif. Our data suggest that Jade-1S phosphorylation at an N-terminal CK1a motif creates a PLK1 phospho-binding domain. We propose CK1a phosphorylation of Jade 1S to serve as a molecular switch, turning off chromatin remodelling functions of Jade-1S and allowing timely cell cycle progression. As Jade-1S protein expression in the kidney is altered upon renal injury, this could contribute to understanding mechanisms underlying epithelial injury repair.

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“…Rozdílná tkáňově specifi cká exprese Plk je důležitým faktorem pro možnou budoucí klinickou aplikaci vyvíjených inhibitorů Plk1. Podrobnější informace o fyziologických funkcích Plk1 lze nalézt v přehledových článcích zahraničních autorů [32][33][34].…”

Section: Rodina Proteinů Polo-like Kinázunclassified

Polo-like Kinase 1 as a Target for Anti-tumor Therapy

Procházková¹,

Vojtěšek²

2015

Klin Onkol

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Regionální centrum aplikované molekulární onkologie, Masarykův onkologický ústav, Brno SouhrnJednotlivé proteiny z rodiny polo-like kináz (Plk) plní rozdílné, avšak kritické funkce při regulaci buněčného cyklu a koordinují buněčnou odpověď na poškození DNA. Nejvíce prostudovaným z pěti členů této rodiny je protein Plk1. Jedná se o serin/ treonin kinázu, která hraje klíčovou roli v mnoha fázích mitózy, a s její deregulací se setkáváme u různých typů nádorů, kde je její zvýšená hladina většinou asociována s horší prognózou. Z pohledu léčby je také zajímavý vztah Plk1 a proteinu p53. Nejen z těchto důvodů se Plk1 stala jedním z atraktivních cílů pro vývoj protinádorových léčiv. Nejnadějněji se nyní jeví inhibitor ATP-vazebné oblasti Plk1 volasertib (BI 6727), který v doposud provedených klinických studiích prodloužil přežití pa cientů s akutní myeloidní leukemií a nyní je testován v klinické studii fáze III. Ve fázi preklinického testování se nachází také několik inhibitorů polo-box domény (druhého možného místa inhibice polo-like kináz), které by měly zajistit větší specifi tu vůči Plk1. Klíčová slovapolo-like kináza 1 -nádorový supresor p53 -ATP-kompetitivní inhibitory -polo-box doména -klinické studie SummaryIndividual proteins from polo-like kinase (Plk) family fulfi l diff erent but critical functions in regulating cell cycle and coordinate cell response to DNA-damage. The most studied one from this fi ve-member family is Plk1. It is a serine/ threonine kinase that plays a pivotal role in many aspects of mitosis and its deregulation is common in various tumor types where the elevated level is mostly associated with worse prognosis. From the therapeutical point of view, intertwin ed relationship between Plk1 and p53 protein is very interesting and will be discussed. Not only for these reasons, Plk1 has become an attractive target for anti-tumor drug development. The most promising seems to be ATP-binding site inhibitor Volasertib (BI 6727) which provided a survival benefi t for patients with acute myeloid leukemia and is now tested in phase III clinical trial. A new generation of Plk1 inhibitors that target the second druggable domain of Plk1, the polo-box domain, is currently being tested preclinically and are believed to improve Plk1 specifi city.

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Polo-like kinase-1 in DNA damage response

Cited by 53 publications

References 84 publications

Whole Transcriptome Analysis of Pre-invasive and Invasive Early Squamous Lung Carcinoma in Archival Laser Microdissected Samples

Whole Transcriptome Analysis of Pre-invasive and Invasive Early Squamous Lung Carcinoma in Archival Laser Microdissected Samples

Jade-1S phosphorylation induced by CK1α contributes to cell cycle progression

Polo-like Kinase 1 as a Target for Anti-tumor Therapy

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