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Polo-like kinase

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https://www.readbyqxmd.com/read/29035889/inhibition-of-suicidal-erythrocyte-death-by-volasertib
#1
Abdulla Al Mamun Bhuyan, A K M Ashiqul Haque, Itishri Sahu, Hang Cao, Michael S D Kormann, Florian Lang
BACKGROUND/AIMS: The Polo-like kinase 1 (Plk1) inhibitor volasertib is used in the treatment of malignancy. Volasertib is partially effective by triggering suicidal death or apoptosis of tumor cells. Similar to apoptosis of nucleated cells, erythrocytes may enter suicidal cell death or eryptosis, which is characterized by cell membrane scrambling with phosphatidylserine translocation to the cell surface and by cell shrinkage. Stimulators of eryptosis include energy depletion, hyperosmotic shock, oxidative stress and excessive increase of cytosolic Ca2+ activity ([Ca2+]i)...
October 16, 2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29030058/mdm2-antagonists-counteract-drug-induced-dna-damage
#2
Anna E Vilgelm, Priscilla Cobb, Kiran Malikayil, David Flaherty, C Andrew Johnson, Dayanidhi Raman, Nabil Saleh, Brian Higgins, Brandon A Vara, Jeffrey N Johnston, Douglas B Johnson, Mark C Kelley, Sheau-Chiann Chen, Gregory D Ayers, Ann Richmond
Antagonists of MDM2-p53 interaction are emerging anti-cancer drugs utilized in clinical trials for malignancies that rarely mutate p53, including melanoma. We discovered that MDM2-p53 antagonists protect DNA from drug-induced damage in melanoma cells and patient-derived xenografts. Among the tested DNA damaging drugs were various inhibitors of Aurora and Polo-like mitotic kinases, as well as traditional chemotherapy. Mitotic kinase inhibition causes mitotic slippage, DNA re-replication, and polyploidy. Here we show that re-replication of the polyploid genome generates replicative stress which leads to DNA damage...
September 19, 2017: EBioMedicine
https://www.readbyqxmd.com/read/28973348/plk1-mediated-phosphorylation-of-wdr62-mcph2-ensures-proper-mitotic-spindle-orientation
#3
Tatsuo Miyamoto, Silvia Natsuko Akutsu, Akihiro Fukumitsu, Hiroyuki Morino, Yoshinori Masatsuna, Kosuke Hosoba, Hideshi Kawakami, Takashi Yamamoto, Kenji Shimizu, Hirofumi Ohashi, Shinya Matsuura
Primary microcephaly (MCPH) is an autosomal recessive disorder characterized by congenital reduction of head circumference. Here, we identified compound heterozygous mutations c.731 C>T (p.Ser 244 Leu) and c.2413G>T (p.Glu 805 X) in the WDR62/MCPH2 gene, which encodes the mitotic centrosomal protein WDR62, in two siblings in a Japanese family with microcephaly using whole-exome sequencing. However, the molecular and cellular pathology of microcephaly caused by WDR62/MCPH2 mutation remains unclear. To clarify the physiological role of WDR62, we used the CRISPR/Cas9 system and single-stranded oligonucleotides as a point-mutation-targeting donor to generate human cell lines with knock-in of WDR62/MCPH2 c...
August 26, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28953239/the-emerging-role-of-polo-like-kinase-1-in-epithelial-mesenchymal-transition-and-tumor-metastasis
#4
REVIEW
Zheng Fu, Donghua Wen
Polo-like kinase 1 (PLK1) is a serine/threonine kinase that plays a key role in the regulation of the cell cycle. PLK1 is overexpressed in a variety of human tumors, and its expression level often correlates with increased cellular proliferation and poor prognosis in cancer patients. It has been suggested that PLK1 controls cancer development through multiple mechanisms that include canonical regulation of mitosis and cytokinesis, modulation of DNA replication, and cell survival. However, emerging evidence suggests novel and previously unanticipated roles for PLK1 during tumor development...
September 27, 2017: Cancers
https://www.readbyqxmd.com/read/28933595/phosphoproteome-based-kinase-activity-profiling-reveals-the-critical-role-of-map2k2-and-plk1-in-neuronal-autophagy
#5
Lei-Lei Chen, Yong-Bo Wang, Ju-Xian Song, Wan-Kun Deng, Jia-Hong Lu, Li-Li Ma, Chuan-Bin Yang, Min Li, Yu Xue
Recent studies have demonstrated that dysregulation of macroautophagy/autophagy may play a central role in the pathogenesis of neurodegenerative disorders, and the induction of autophagy protects against the toxic insults of aggregate-prone proteins by enhancing their clearance. Thus, autophagy has become a promising therapeutic target against neurodegenerative diseases. In this study, quantitative phosphoproteomic profiling together with a computational analysis was performed to delineate the phosphorylation signaling networks regulated by 2 natural neuroprotective autophagy enhancers, corynoxine (Cory) and corynoxine B (Cory B)...
September 21, 2017: Autophagy
https://www.readbyqxmd.com/read/28930533/53bp1-a-guardian-for-centrosomal-integrity
#6
Haeyoung Kim, Hyungshin Yim
53BP1 is known as a mediator in DNA damage response and a regulator of DNA double-stranded breaks (DSBs) repair. 53BP1 was recently reported to be a centrosomal protein and a binding partner of mitotic polo-like kinase 1 (Plk1). The stability of 53BP1, in response to DSBs, is regulated by its phosphorylation, deubiquitination, and ubiquitination. During mitosis, 53BP1 is stabilized by phosphorylation at S380, a putative binding region with polo-box domain of Plk1, and deubiquitination by ubiquitin-specific protease 7 (USP7)...
January 1, 2018: Frontiers in Bioscience (Landmark Edition)
https://www.readbyqxmd.com/read/28920432/plk1-targeted-fluorescent-tumor-imaging-with-high-signal-background-ratio
#7
Ji-Ting Hou, Kyung-Phil Ko, Hu Shi, Wen Xiu Ren, Peter Verwilst, Seyoung Koo, Jin Yong Lee, Sung-Gil Chi, Jong Seung Kim
As significantly expressed during cell division, polo-like kinase 1 (PLK1) plays crucial roles in numerous mitotic events and has attracted interest as a potential therapeutic marker in oncological drug discovery. We prepared two small molecular fluorescent probes, 1 and 2, conjugated to SBE13 (a type II PLK1 inhibitor) to investigate the PLK1-targeted imaging of cancer cells and tumors. Enzymatic docking studies, molecular dynamics simulations, in vitro and in vivo imaging experiments, all supported the selective targeting and visualization of PLK1 expressing cells by probes 1 and 2, and probe 2 was successfully demonstrated to image PLK1-upregualted tumors with a remarkable signal to background ratios...
September 18, 2017: ACS Sensors
https://www.readbyqxmd.com/read/28915707/augmented-expression-of-polo-like-kinase-1-indicates-poor-clinical-outcome-for-breast-patients-a-systematic-review-and-meta-analysis
#8
REVIEW
Yunfeng Zhang, Zhibin Wu, Dapeng Liu, Meng Wang, Guodong Xiao, Peili Wang, Xin Sun, Hong Ren, Shou-Ching Tang, Ning Du
Polo-like kinases 1 (PLK1), a key regulator of mitosis, plays an essential role in maintaining genomic stability. Up-regulation of PLK1 was found in tumorigenesis and tumor progression of diverse cancers. However, the clinicopathological and prognostic implications of PLK1 in breast cancer (BC) have yet to be unveiled. Therefore, using PubMed, Web of Science, Embase, and Chinese databases, we conducted a meta-analysis to define the potential clinical value of PLK1 in BC. Eleven eligible articles with 2481 patients enrolled were included in the present meta-analysis, of which eight studies reported on the relationship between PLK1 expression and clinicopathological features, and nine studies provided survival data in BC patients...
August 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28912176/anexelekto-mer-tyrosine-kinase-inhibitor-ono-7475-growth-arrests-and-kills-fms-like-tyrosine-kinase-3-internal-tandem-duplication-mutant-acute-myeloid-leukemia-cells-by-diverse-mechanisms
#9
Peter P Ruvolo, Huaxian Ma, Vivian R Ruvolo, Xiaorui Zhang, Hong Mu, Wendy Schober, Ivonne Hernandez, Miguel Gallardo, Joseph Khoury, Jorge Cortes, Michael Andreeff, Sean M Post
Nearly one-third of patients with acute myeloid leukemia have FMS-Like Tyrosine Kinase 3 mutations and thus have poor survival prospects. Receptor tyrosine kinase Anexelekto is critical for FMS-Like Tyrosine Kinase 3 signaling and participates in FMS-Like Tyrosine Kinase 3 inhibitor resistance mechanisms. Thus, strategies targeting Anexelekto could prove useful for acute myeloid leukemia therapy. ONO-7475 is an inhibitor with high specificity for Anexelekto and MER Tyrosine Kinase. Here we report that ONO-7475 potently arrested growth and induced apoptosis in acute myeloid leukemia with internal tandem duplication mutation of FMS-Like Tyrosine Kinase 3...
September 14, 2017: Haematologica
https://www.readbyqxmd.com/read/28901377/anthocyanin%C3%A2-rich-blackcurrant-extract-inhibits-proliferation-of-the-mcf10a-healthy-human-breast-epithelial-cell-line-through-induction-of-g0-g1-arrest-and-apoptosis
#10
Naoki Nanashima, Kayo Horie, Mitsuru Chiba, Manabu Nakano, Hayato Maeda, Toshiya Nakamura
Blackcurrants (Ribes nigrum L., Grossulariaceae) possess a high content of anthocyanin polyphenols, which have been demonstrated to exhibit beneficial effects on health due to their antioxidant and anticarcinogenic prope-rties. The present study investigated novel functions of anthocyanin‑rich blackcurrant extracts (BCEs) in a healthy mammary epithelial cell line, MCF10A. The percentages of viable cells were 85, 75, 53 and 31% following exposure to 50, 100, 200 and 400 µg/ml BCE, respectively. The half‑maximal response concentration of BCE was 237...
August 29, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28900036/polo-like-kinase-1-plk1-overexpression-enhances-ionizing-radiation-induced-cancer-formation-in-mice
#11
Zhiguo Li, Jinghui Liu, Jie Li, Yifan Kong, George Sandusky, Xi Rao, Yunlong Liu, Jun Wan, Xiaoqi Liu
Polo-like kinase 1 (Plk1), a serine/threonine protein kinase normally expressed in mitosis, is frequently upregulated in multiple types of human tumors regardless of the cell cycle stage. However, the causal relationship between Plk1 upregulation and tumorigenesis is incompletely investigated. To this end, using a conditional expression system, here we generated Plk1 transgenic mouse lines to examine Plk1 role in tumorigenesis. Plk1 overexpression in mouse embryonic fibroblasts prepared from the transgenic mice led to aberrant mitosis followed by aneuploidy and apoptosis...
September 12, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28884018/pp2a-b-holoenzyme-substrate-recognition-regulation-and-role-in-cytokinesis
#12
Cheng-Guo Wu, Hui Chen, Feng Guo, Vikash K Yadav, Sean J Mcilwain, Michael Rowse, Alka Choudhary, Ziqing Lin, Yitong Li, Tingjia Gu, Aiping Zheng, Qingge Xu, Woojong Lee, Eduard Resch, Benjamin Johnson, Jenny Day, Ying Ge, Irene M Ong, Mark E Burkard, Ylva Ivarsson, Yongna Xing
Protein phosphatase 2A (PP2A) is a major Ser/Thr phosphatase; it forms diverse heterotrimeric holoenzymes that counteract kinase actions. Using a peptidome that tiles the disordered regions of the human proteome, we identified proteins containing [LMFI]xx[ILV]xEx motifs that serve as interaction sites for B'-family PP2A regulatory subunits and holoenzymes. The B'-binding motifs have important roles in substrate recognition and in competitive inhibition of substrate binding. With more than 100 novel ligands identified, we confirmed that the recently identified LxxIxEx B'α-binding motifs serve as common binding sites for B' subunits with minor variations, and that S/T phosphorylation or D/E residues at positions 2, 7, 8 and 9 of the motifs reinforce interactions...
2017: Cell Discovery
https://www.readbyqxmd.com/read/28867728/development-of-a-high-throughput-assay-for-inhibitors-of-the-polo-box-domain-of-polo-like-kinase-1-based-on-time-resolved-fluorescence-energy-transfer
#13
Tae Gi Kim, Ju Hee Lee, Mi Young Lee, Ka-Ul Kim, Jeong Hyun Lee, Chi Hoon Park, Byung Ho Lee, Kwang-Seok Oh
Although enzyme-linked immunosorbent assay (ELISA) technology has been widely accepted for binding assays against the polo-box domain (PBD) of polo-like kinase-1 (Plk1), these assays have a limitation-related heterogeneous procedure, such as multiple incubations and washing steps to apply high-throughput screenings (HTSs). In the present study, a Plk1-PBD binding assay based on time-resolved fluorescence energy transfer (TR-FRET) was developed for HTS of PBD-binding inhibitors. The TR-FRET-based Plk1-PBD binding assay is sensitive and robust and can be miniaturized into the 384-well plate-based format...
2017: Biological & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/28858266/kinases-involved-in-both-autophagy-and-mitosis
#14
REVIEW
Zhiyuan Li, Xin Zhang
Both mitosis and autophagy are highly regulated dynamic cellular processes and involve various phosphorylation events catalysed by kinases, which play vital roles in almost all physiological and pathological conditions. Mitosis is a key event during the cell cycle, in which the cell divides into two daughter cells. Autophagy is a process in which the cell digests its own cellular contents. Although autophagy regulation has mainly been studied in asynchronous cells, increasing evidence indicates that autophagy is in fact tightly regulated in mitosis...
August 31, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28857653/polo-like-kinase-3-hypoxic-responses-and-tumorigenesis
#15
Dazhong Xu, Wei Dai, Cen Li
The cellular hypoxic response contributes to cell transformation and tumor progression. Hypoxia-inducible factor 1 (HIF-1) is a key transcription factor that mediates transcription of genes whose products are essential for cellular adaptation to hypoxia. The activity of HIF-1 is largely regulated by the abundance of its alpha subunit (HIF-1α), which is primarily regulated by an oxygen-dependent and ubiquitin/proteasome-mediated degradation process. The HIF-1α protein level is also regulated by protein kinases through phosphorylation...
August 31, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28853395/polo-like-kinase-cdc5-regulates-spc72-recruitment-to-spindle-pole-body-in-the-methylotrophic-yeast-ogataea-polymorpha
#16
Hiromi Maekawa, Annett Neuner, Diana Rüthnick, Elmar Schiebel, Gislene Pereira, Yoshinobu Kaneko
Cytoplasmic microtubules (cMT) control mitotic spindle positioning in many organisms, and are therefore pivotal for successful cell division. Despite its importance, the temporal control of cMT formation remains poorly understood. Here we show that unlike the best-studied yeast Saccharomyces cerevisiae, position of pre-anaphase nucleus is not strongly biased toward bud neck in Ogataea polymorpha and the regulation of spindle positioning becomes active only shortly before anaphase. This is likely due to the unstable property of cMTs compared to those in S...
August 30, 2017: ELife
https://www.readbyqxmd.com/read/28851440/plk1-is-essential-for-proper-chromosome-segregation-during-meiosis-i-meiosis-ii-transition-in-pig-oocytes
#17
Zixiao Zhang, Changchao Chen, Liying Ma, Qiuchen Yu, Shuai Li, Benazir Abbasi, Jiayi Yang, Rong Rui, Shiqiang Ju
BACKGROUND: Polo-like kinase 1 (Plk1), as a characteristic regulator in meiosis, organizes multiple biological events of cell division. Although Plk1 has been implicated in various functions in somatic cell mitotic processes, considerably less is known regarding its function during the transition from metaphase I (MI) to metaphase II (MII) stage in oocyte meiotic progression. METHODS: In this study, the possible role of Plk1 during the MI-to-MII stage transition in pig oocytes was addressed...
August 29, 2017: Reproductive Biology and Endocrinology: RB&E
https://www.readbyqxmd.com/read/28843004/single-nucleotide-polymorphisms-rs911160-in-aurka-and-rs2289590-in-aurkb-mitotic-checkpoint-genes-contribute-to-gastric-cancer-susceptibility
#18
Aner Mesic, Ela Markocic, Marija Rogar, Robert Juvan, Petra Hudler, Radovan Komel
BACKGROUND: Single nucleotide polymorphisms (SNPs) in mitotic checkpoint genes could confer increased susceptibility to gastric cancer (GC). We investigated the association of Aurora kinase A (AURKA), Aurora kinase B (AURKB), Aurora kinase C (AURKC), Polo-like kinase 1 (PLK1) and Budding uninhibited by benzimidazol 3, yeast (BUB3) gene polymorphisms with GC risk. MATERIALS AND METHODS: Genotyping of 6 SNPs in AURKA (rs911160 and rs8173), AURKB (rs2289590), AURKC (rs11084490), PLK1 (rs42873), and BUB3 (rs7897156) was performed using TaqMan genotyping assays...
August 26, 2017: Environmental and Molecular Mutagenesis
https://www.readbyqxmd.com/read/28836854/an-update-on-the-developing-mitotic-inhibitors-for-the-treatment-of-non-small-cell-carcinoma
#19
REVIEW
Paola Claudia Sacco, Cesare Gridelli
Mitosis is necessary to sustain life and is followed immediately by cell division into two daughter cells. Microtubules play a key role in the formation of the mitotic spindle apparatus and cytokinesis at the end of mitosis. Various anti-microtubule agents such as taxanes and vinca alkaloids are widely used in the treatment of advanced non-small cell lung cancer (NSCLC) but their use is associated with hematologic toxicity profile, acquired resistance and hypersensitivity reactions. Areas covered: The Nab-paclitaxels are the more recent antimitotic agents approved in NSCLC showing a better tolerability and activity when compared to previous ones...
September 2017: Expert Opinion on Emerging Drugs
https://www.readbyqxmd.com/read/28832566/analysis-of-centrosome-and-dna-damage-response-in-plk4-associated-seckel-syndrome
#20
Tuba Dinçer, Gülden Yorgancıoğlu-Budak, Akgün Ölmez, İdris Er, Yavuz Dodurga, Özmert Ma Özdemir, Bayram Toraman, Adem Yıldırım, Nuran Sabir, Nurten A Akarsu, C Nur Semerci, Ersan Kalay
Microcephalic primordial dwarfism (MPD) is a group of autosomal recessive inherited single-gene disorders with intrauterine and postnatal global growth failure. Seckel syndrome is the most common form of the MPD. Ten genes are known with Seckel syndrome. Using genome-wide SNP genotyping and homozygosity mapping we mapped a Seckel syndrome gene to chromosomal region 4q28.1-q28.3 in a Turkish family. Direct sequencing of PLK4 (polo-like kinase 4) revealed a homozygous splicing acceptor site transition (c.31-3 A>G) that results in a premature translation termination (p...
October 2017: European Journal of Human Genetics: EJHG
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