scholarly journals Role for polo-like kinase 4 in mediation of cytokinesis

2019 ◽  
Vol 116 (23) ◽  
pp. 11309-11318 ◽  
Author(s):  
Michael F. Press ◽  
Bin Xie ◽  
Simon Davenport ◽  
Yu Zhou ◽  
Roberta Guzman ◽  
...  
Keyword(s):  
Cell Division ◽  
Kinase Activity ◽  
Critical Role ◽  
Mitotic Catastrophe ◽  
Centrosome Duplication ◽  
Cleavage Furrow ◽  
Molecule Inhibitor ◽  
Colorectal Cancer Cells ◽  
Spindle Midzone

The mitotic protein polo-like kinase 4 (PLK4) plays a critical role in centrosome duplication for cell division. By using immunofluorescence, we confirm that PLK4 is localized to centrosomes. In addition, we find that phospho-PLK4 (pPLK4) is cleaved and distributed to kinetochores (metaphase and anaphase), spindle midzone/cleavage furrow (anaphase and telophase), and midbody (cytokinesis) during cell division in immortalized epithelial cells as well as breast, ovarian, and colorectal cancer cells. The distribution of pPLK4 midzone/cleavage furrow and midbody positions pPLK4 to play a functional role in cytokinesis. Indeed, we found that inhibition of PLK4 kinase activity with a small-molecule inhibitor, CFI-400945, prevents translocation to the spindle midzone/cleavage furrow and prevents cellular abscission, leading to the generation of cells with polyploidy, increased numbers of duplicated centrosomes, and vulnerability to anaphase or mitotic catastrophe. The regulatory role of PLK4 in cytokinesis makes it a potential target for therapeutic intervention in appropriately selected cancers.

scholarly journals A critical role for IRAK4 kinase activity in Toll-like receptor–mediated innate immunity

2007 ◽  
Vol 204 (5) ◽  
pp. 1025-1036 ◽  
Author(s):  
Tae Whan Kim ◽  
Kirk Staschke ◽  
Katarzyna Bulek ◽  
Jianhong Yao ◽  
Kristi Peters ◽  
...  
Keyword(s):  
Immune Responses ◽  
Kinase Activity ◽  
Critical Role ◽  
Nuclear Factor Κb ◽  
Type I ◽  
Toll Like Receptor ◽  
Chemokine Production ◽  
Cytokines And Chemokines ◽  
Plasmacytoid Dcs

IRAK4 is a member of IL-1 receptor (IL-1R)–associated kinase (IRAK) family and has been shown to play an essential role in Toll-like receptor (TLR)–mediated signaling. We recently generated IRAK4 kinase-inactive knock-in mice to examine the role of kinase activity of IRAK4 in TLR-mediated signaling pathways. The IRAK4 kinase–inactive knock-in mice were completely resistant to lipopolysaccharide (LPS)- and CpG-induced shock, due to impaired TLR-mediated induction of proinflammatory cytokines and chemokines. Although inactivation of IRAK4 kinase activity did not affect the levels of TLR/IL-1R–mediated nuclear factor κB activation, a reduction of LPS-, R848-, and IL-1–mediated mRNA stability contributed to the reduced cytokine and chemokine production in bone marrow–derived macrophages from IRAK4 kinase–inactive knock-in mice. Both TLR7- and TLR9-mediated type I interferon production was abolished in plasmacytoid dendritic cells isolated from IRAK4 knock-in mice. In addition, influenza virus–induced production of interferons in plasmacytoid DCs was also dependent on IRAK4 kinase activity. Collectively, our results indicate that IRAK4 kinase activity plays a critical role in TLR-dependent immune responses.

scholarly journals Critical role of kinase activity of hematopoietic progenitor kinase 1 in anti-tumor immune surveillance

PLoS ONE ◽  
2019 ◽  
Vol 14 (3) ◽  
pp. e0212670 ◽  
Author(s):  
Jinqi Liu ◽  
Joshua Curtin ◽  
Dan You ◽  
Stephen Hillerman ◽  
Bifang Li-Wang ◽  
...  
Keyword(s):  
Kinase Activity ◽  
Critical Role ◽  
Immune Surveillance ◽  
Hematopoietic Progenitor

325 CELF2 Induced Splicing Results in Loss of the Bir Domain in Survivin: Critical Role of XIAP in Radiation Induced Mitotic Catastrophe

2012 ◽  
Vol 142 (5) ◽  
pp. S-75
Author(s):  
David Standing ◽  
Prabhu Ramamoorthy ◽  
Parthasarathy Rangarajan ◽  
Dharmalingam Subramaniam ◽  
Satish Ramalingam ◽  
...  
Keyword(s):  
Critical Role ◽  
Mitotic Catastrophe ◽  
Radiation Induced ◽  
Bir Domain

scholarly journals Systematic analysis of atx-2 suppressors reveals a novel regulator of PAR-5/14-3-3sigma function during mitosis in Caenorhabditis elegans

2017 ◽  
Author(s):  
Megan M. Gnazzo ◽  
Alex R. Villarreal ◽  
Ahna R. Skop
Keyword(s):  
Cell Division ◽  
Rna Binding ◽  
Critical Role ◽  
Neuronal Function ◽  
Rna Regulation ◽  
Systematic Analysis ◽  
Dead Box ◽  
Rnai Suppressor ◽  
Function Loss ◽  
Spindle Midzone

AbstractRNA regulation plays a critical role in mitosis, yet the mechanisms remain unclear. Our lab recently identified that the conserved RNA-Binding Protein (RBP), ATX-2, regulates cytokinesis by regulating the targeting of ZEN-4 to the spindle midzone through a conserved translation regulator, PAR-5/14-3-3sigma (Gnazzo et al., 2016). While co-depletion of ATX-2 and PAR-5 restored ZEN-4 targeting to the spindle midzone, it did not rescue cell division. To identify factors that may work in concert with ATX-2 to regulate cell division, we conducted a two-part, candidate RNAi suppressor and visual screen to identify factors that are important for cell division and also mediate the targeting of ATX-2 to the centrosomes and the spindle midzone. Using this approach, we identified ten genes that suppress the embryonic lethality defect observed in atx-2 mutant embryos. These ten genes, including act-2, cgh-1, cki-1, hum-6, par-2, rnp-4, vab-3, vhl-1, vps-24, and wve-1, all have some role regulating RNA or the cell cycle. Five of these genes (cgh-1, cki-1, vab-3, vhl-1, vps-24) fail to target ATX-2 to the centrosomes and midzone when depleted. The strongest suppressor of the atx-2 phenotype is the DEAD-box RNA helicase CGH-1/DDX6, which has been implicated in cell division, RNA processing and translation, and neuronal function. Loss of CGH-1 rescued the cytokinesis defect and also restored ZEN-4 localization to the spindle midzone. ATX-2 and CGH-1 are mutually required for their localization to centrosomes and the spindle midzone. Our findings provide the first functional evidence that CGH-1/DDX6 regulates ATX-2 function during mitosis to target ZEN-4 to the spindle midzone via PAR-5/14-3-3sigma. We suggest that RNA machinery is necessary for the completion of cytokinesis.

scholarly journals Phosphoproteome-based kinase activity profiling reveals the critical role of MAP2K2 and PLK1 in neuronal autophagy

Autophagy ◽  
2017 ◽  
Vol 13 (11) ◽  
pp. 1969-1980 ◽  
Author(s):  
Lei-Lei Chen ◽  
Yong-Bo Wang ◽  
Ju-Xian Song ◽  
Wan-Kun Deng ◽  
Jia-Hong Lu ◽  
...  
Keyword(s):  
Kinase Activity ◽  
Critical Role ◽  
Activity Profiling ◽  
Neuronal Autophagy

The critical role of kinase activity of interleukin-1 receptor-associated kinase 4 in animal models of joint inflammation

2009 ◽  
Vol 60 (6) ◽  
pp. 1661-1671 ◽  
Author(s):  
Magdalena Koziczak-Holbro ◽  
Amanda Littlewood-Evans ◽  
Bernadette Pöllinger ◽  
Jiri Kovarik ◽  
Janet Dawson ◽  
...  
Keyword(s):  
Animal Models ◽  
Kinase Activity ◽  
Interleukin 1 ◽  
Critical Role ◽  
Joint Inflammation

scholarly journals BET bromodomain inhibition suppresses TH17-mediated pathology

2013 ◽  
Vol 210 (11) ◽  
pp. 2181-2190 ◽  
Author(s):  
Deanna A. Mele ◽  
Andres Salmeron ◽  
Srimoyee Ghosh ◽  
Hon-Ren Huang ◽  
Barbara M. Bryant ◽  
...  
Keyword(s):  
Th17 Cells ◽  
Bacterial Infections ◽  
Critical Role ◽  
Dependent Manner ◽  
Bet Inhibitor ◽  
Molecule Inhibitor ◽  
Autoimmune Conditions ◽  
Th17 Differentiation

Interleukin (IL) 17–producing T helper (TH17) cells have been selected through evolution for their ability to control fungal and bacterial infections. It is also firmly established that their aberrant generation and activation results in autoimmune conditions. Using a characterized potent and selective small molecule inhibitor, we show that the bromodomain and extra-terminal domain (BET) family of chromatin adaptors plays fundamental and selective roles in human and murine TH17 differentiation from naive CD4+ T cells, as well as in the activation of previously differentiated TH17 cells. We provide evidence that BET controls TH17 differentiation in a bromodomain-dependent manner through a mechanism that includes the direct regulation of multiple effector TH17-associated cytokines, including IL17, IL21, and GMCSF. We also demonstrate that BET family members Brd2 and Brd4 associate with the Il17 locus in TH17 cells, and that this association requires bromodomains. We recapitulate the critical role of BET bromodomains in TH17 differentiation in vivo and show that therapeutic dosing of the BET inhibitor is efficacious in mouse models of autoimmunity. Our results identify the BET family of proteins as a fundamental link between chromatin signaling and TH17 biology, and support the notion of BET inhibition as a point of therapeutic intervention in autoimmune conditions.

scholarly journals Double-Stranded RNA Dependent Kinase R Regulates Antibacterial Immunity in Sepsis

2020 ◽  
pp. 1-12
Author(s):  
Yanliang Yang ◽  
Lingli Xie ◽  
Yanjun Zhong ◽  
Xiaoli Zhong ◽  
Ran Meng ◽  
...  
Keyword(s):  
Kinase Activity ◽  
Critical Role ◽  
Cecal Ligation ◽  
Organ Injury ◽  
Cecal Ligation And Puncture ◽  
Bacterial Sepsis ◽  
Double Stranded Rna ◽  
Important Regulator ◽  
Genetic Deletion

Double-stranded RNA dependent kinase R (PKR) is originally identified as an intracellular sensor of viral infection, but its role in bacterial infection remains largely unknown. Here we report that PKR was an important regulator of antibacterial immunity in sepsis. Genetic deletion of PKR or pharmacological inhibition of its kinase activity markedly increased bacterial loads, organ injury, and mortality in polymicrobial infection induced by cecal ligation and puncture (CLP). In contrast, PKR deficiency or inhibition did not affect bacterial loads, organ injury, or mortality when mice were systemically challenged with <i>Escherichia coli</i>, an abundant microbe in the gastrointestinal tract. PKR deficiency or inhibition markedly decreased the release of interleukin (IL)-1β after CLP. Defect in IL-1 signaling phenocopied PKR deficiency or inhibition in CLP-induced bacterial sepsis. Taken together, these findings identified a critical role of the PKR signaling pathway in antibacterial immunity.

scholarly journals The role of Lyn kinase in the development of imatinib resistance in chronic myelogenous leukemia

2011 ◽  
Vol 2 (2) ◽  
pp. 67
Author(s):  
Camillo Porta ◽  
Federica Tagliani
Keyword(s):  
Cost Effectiveness ◽  
Chronic Myelogenous Leukemia ◽  
Small Molecule ◽  
Kinase Activity ◽  
Myelogenous Leukemia ◽  
Tyrosine Kinase Activity ◽  
Imatinib Resistance ◽  
Lyn Kinase ◽  
Molecule Inhibitor

Imatinib mesylate, a small-molecule inhibitor of BCRABL tyrosine kinase activity, has emerged as the well-recognized standard of treatment for chronic myelogenous leukemia (CML). Indeed, both its efficacy, tolerability, as well as cost-effectiveness have been clearly proven...

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