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  • Polo kinase links the stress pathway to cell cycle control and tip growth in fission yeast. 15917811

    Stress-activated mitogen-activated protein kinase cascades instigate a range of changes to enable eukaryotic cells to cope with particular insults. In Schizosaccharomyces pombe these responses include the transcription of specific gene sets and inhibition of entry into mitosis. The S. pombe stress response pathway (SRP) also promotes commitment to mitosis in unperturbed cell cycles to allow cells to match their rate of division with nutrient availability. The nature of this SRP function in cell cycle control is unknown. Entry into mitosis is controlled by mitosis-promoting factor (MPF; Cdc2/cyclin B) activity. Inhibitory phosphorylation of Cdc2 by Wee1 kinase inactivates MPF until Cdc25 removes this phosphate to promote mitosis. The balance between Wee1 and Cdc25 activities is influenced by the recruitment of polo kinase (Plo1) to the spindle pole body (SPB). The SPB component Cut12 mediates this recruitment. Hyper-activating mutations in either cut12 or plo1 enable Cdc25-defective cells to enter mitosis. The hyperactive cut12.s11 mutation suppresses cdc25.22, as it promotes recruitment of active Plo1 to interphase SPBs. Here we show that the SRP promotes phosphorylation of Plo1 on Ser 402. In unperturbed cell cycles, SRP-mediated phosphorylation of Ser 402 promotes Plo1 recruitment to SPBs and thus commitment to mitosis. Ser 402 phosphorylation also ensures efficient reinitiation of cell tip growth and cell division during recovery from particular stresses. Thus, phosphorylation of Plo1 Ser 402 not only enables SRP signalling to modulate the timing of mitotic commitment in response to nutrient status in unperturbed cycles, but also promotes the return to normal cell cycle control after stress.
    Tipo de documento:
    Referencia
    Referencia del producto:
    05-321X
    Nombre del producto:
    Anti-Phosphotyrosine Antibody, clone 4G10®

  • Relocation of Aurora B from centromeres to the central spindle at the metaphase to anaphase transition requires MKlp2. 15263015

    Mitotic kinases of the Polo and Aurora families are key regulators of chromosome segregation and cytokinesis. Here, we have investigated the role of MKlp1 and MKlp2, two vertebrate mitotic kinesins essential for cytokinesis, in the spatial regulation of the Aurora B kinase. Previously, we have demonstrated that MKlp2 recruits Polo-like kinase 1 (Plk1) to the central spindle in anaphase. We now find that in MKlp2 but not MKlp1-depleted cells the Aurora B-INCENP complex remains at the centromeres and fails to relocate to the central spindle. MKlp2 exerts dual control over Aurora B localization, because it is a binding partner for Aurora B, and furthermore for the phosphatase Cdc14A. Cdc14A can dephosphorylate INCENP and may contribute to its relocation to the central spindle in anaphase. We propose that MKlp2 is involved in the localization of Plk1, Aurora B, and Cdc14A to the central spindle during anaphase, and that the integration of signaling by these proteins is necessary for proper cytokinesis.
    Tipo de documento:
    Referencia
    Referencia del producto:
    05-940
    Nombre del producto:
    Anti-INCENP Antibody, clone 58-217

  • Plk4 is required for cytokinesis and maintenance of chromosomal stability. 20348415

    Aneuploidy is a characteristic feature of established cancers and can promote tumor development. Aneuploidy may arise directly, through unequal distribution of chromosomes into daughter cells, or indirectly, through a tetraploid intermediate. The polo family kinase Plk4/Sak is required for late mitotic progression and is haploinsufficient for tumor suppression in mice. Here we show that loss of heterozygosity (LOH) occurs at the Plk4 locus in 50% of human hepatocellular carcinomas (HCC) and is present even in preneoplastic cirrhotic liver nodules. LOH at Plk4 is associated with reduced Plk4 expression in HCC tumors but not with mutations in the remaining allele. Plk4(+/-) murine embryonic fibroblasts (MEFs) at early passage show a high incidence of multinucleation, supernumerary centrosomes, and a near-tetraploid karyotype. Underlying these phenotypes is a high rate of primary cytokinesis failure, associated with aberrant actomyosin ring formation, reduced RhoA activation, and failure to localize the RhoA guanine nucleotide exchange factor Ect2 to the spindle midbody. We further show that Plk4 normally localizes to the midbody and binds to and phosphorylates Ect2 in vitro. With serial passaging Plk4(+/-) MEFs rapidly immortalize, acquiring an increasing burden of nonclonal and clonal gross chromosomal irregularities, and form tumors in vivo. Our results indicate that haploid levels of Plk4 disrupt RhoGTPase function during cytokinesis, resulting in aneuploidy and tumorigenesis, thus implicating early LOH at Plk4 as one of the drivers of human hepatocellular carcinogenesis. These findings represent an advance in our understanding of genetic predisposition to HCC, which continues to increase in incidence globally and particularly in North America.
    Tipo de documento:
    Referencia
    Referencia del producto:
    06-813
    Nombre del producto:
    Anti-PLK1 Antibody, NT

  • Sensitivity of cancer cells to Plk1 inhibitor GSK461364A is associated with loss of p53 function and chromosome instability. 20571075

    Polo-like kinases are a family of serine threonine kinases that are critical regulators of cell cycle progression and DNA damage response. Predictive biomarkers for the Plk1-selective inhibitor GSK461364A were identified by comparing the genomics and genetics of a panel of human cancer cell lines with their response to a drug washout followed by an outgrowth assay. In this assay, cell lines that have lost p53 expression or carry mutations in the TP53 gene tended to be more sensitive to GSK461364A. These more sensitive cell lines also had increased levels of chromosome instability, a characteristic associated with loss of p53 function. Further mechanistic studies showed that p53 wild-type (WT) and not mutant cells can activate a postmitotic tetraploidy checkpoint and arrest at pseudo-G(1) state after GSK461364A treatment. RNA silencing of WT p53 increased the antiproliferative activity of GSK461364A. Furthermore, silencing of p53 or p21/CDKN1A weakened the tetraploidy checkpoint in cells that survived mitotic arrest and mitotic slippage. As many cancer therapies tend to be more effective in p53 WT patients, the higher sensitivity of p53-deficient tumors toward GSK461364A could potentially offer an opportunity to treat tumors that are refractory to other chemotherapies as well as early line therapy for these genotypes.
    Tipo de documento:
    Referencia
    Referencia del producto:
    Múltiplo
    Nombre del producto:
    Múltiplo

  • Serine 129 phosphorylation reduces the ability of alpha-synuclein to regulate tyrosine hydroxylase and protein phosphatase 2A in vitro and in vivo. 20356833

    Alpha-synuclein (a-Syn), a protein implicated in Parkinson disease, contributes significantly to dopamine metabolism. a-Syn binding inhibits the activity of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine synthesis. Phosphorylation of TH stimulates its activity, an effect that is reversed by protein phosphatase 2A (PP2A). In cells, a-Syn overexpression activates PP2A. Here we demonstrate that a-Syn significantly inhibited TH activity in vitro and in vivo and that phosphorylation of a-Syn serine 129 (Ser-129) modulated this effect. In MN9D cells, a-Syn overexpression reduced TH serine 19 phosphorylation (Ser(P)-19). In dopaminergic tissues from mice overexpressing human a-Syn in catecholamine neurons only, TH-Ser-19 and TH-Ser-40 phosphorylation and activity were also reduced, whereas PP2A was more active. Cerebellum, which lacks excess a-Syn, had PP2A activity identical to controls. Conversely, a-Syn knock-out mice had elevated TH-Ser-19 phosphorylation and activity and less active PP2A in dopaminergic tissues. Using an a-Syn Ser-129 dephosphorylation mimic, with serine mutated to alanine, TH was more inhibited, whereas PP2A was more active in vitro and in vivo. Phosphorylation of a-Syn Ser-129 by Polo-like-kinase 2 in vitro reduced the ability of a-Syn to inhibit TH or activate PP2A, identifying a novel regulatory role for Ser-129 on a-Syn. These findings extend our understanding of normal a-Syn biology and have implications for the dopamine dysfunction of Parkinson disease.
    Tipo de documento:
    Referencia
    Referencia del producto:
    Múltiplo
    Nombre del producto:
    Múltiplo

  • Extensive crosstalk between O-GlcNAcylation and phosphorylation regulates cytokinesis. 20068230

    Like phosphorylation, the addition of O-linked beta-N-acetylglucosamine (O-GlcNAcylation) is a ubiquitous, reversible process that modifies serine and threonine residues on nuclear and cytoplasmic proteins. Overexpression of the enzyme that adds O-GlcNAc to target proteins, O-GlcNAc transferase (OGT), perturbs cytokinesis and promotes polyploidy, but the molecular targets of OGT that are important for its cell cycle functions are unknown. Here, we identify 141 previously unknown O-GlcNAc sites on proteins that function in spindle assembly and cytokinesis. Many of these O-GlcNAcylation sites are either identical to known phosphorylation sites or in close proximity to them. Furthermore, we found that O-GlcNAcylation altered the phosphorylation of key proteins associated with the mitotic spindle and midbody. Forced overexpression of OGT increased the inhibitory phosphorylation of cyclin-dependent kinase 1 (CDK1) and reduced the phosphorylation of CDK1 target proteins. The increased phosphorylation of CDK1 is explained by increased activation of its upstream kinase, MYT1, and by a concomitant reduction in the transcript for the CDK1 phosphatase, CDC25C. OGT overexpression also caused a reduction in both messenger RNA expression and protein abundance of Polo-like kinase 1, which is upstream of both MYT1 and CDC25C. The data not only illustrate the crosstalk between O-GlcNAcylation and phosphorylation of proteins that are regulators of crucial signaling pathways but also uncover a mechanism for the role of O-GlcNAcylation in regulation of cell division.
    Tipo de documento:
    Referencia
    Referencia del producto:
    05-368
    Nombre del producto:
    Anti-phospho-Ser/Thr-Pro MPM-2 Antibody

  • Polo-like kinase 2 is a mediator of hedgehog survival signaling in cholangiocarcinoma. 23703673

    Cholangiocarcinoma (CCA) cells paradoxically express the death ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and thus rely on potent survival signals to circumvent cell death by TRAIL. Hedgehog (Hh) signaling is an important survival pathway in CCA. Herein, we further examine the mechanisms whereby Hh signaling mediates apoptosis resistance in CCA, revealing a pivotal role for the cell division regulating serine/threonine kinase polo-like kinase 2 (PLK2). We employed 50 human CCA samples (25 intrahepatic and 25 extrahepatic CCA) as well as human KMCH-1, Mz-CHA-1, and HUCCT-1 CCA cells for these studies. In vivo experiments were conducted using a syngeneic rat orthotopic CCA model. In human samples, polo-like kinase (PLK)1/2/3-immunoreactive cancer cells were present in the preponderance of intra- and extrahepatic CCA specimens. Inhibition of Hh signaling by cyclopamine reduced PLK2, but not PLK1 or PLK3, messenger RNA and protein expression in vehicle-treated and sonic Hh-treated CCA cells, confirming our previous microarray study. PLK2 regulation by Hh signaling appears to be direct, because the Hh transcription factors, glioma-associated oncogene 1 and 2, bind to the PLK2 promotor. Moreover, inhibition of PLK2 by the PLK inhibitor, BI 6727 (volasertib), or PLK2 knockdown was proapoptotic in CCA cells. BI 6727 administration or PLK2 knockdown decreased cellular protein levels of antiapoptotic myeloid cell leukemia 1 (Mcl-1), an effect reversed by the proteasome inhibitor, MG-132. Finally, BI 6727 administration reduced Mcl-1 protein expression in CCA cells, resulting in CCA cell apoptosis and tumor suppression in vivo.PLK2 appears to be an important mediator of Hh survival signaling. These results suggest PLK inhibitors to be of therapeutic value for treatment of human CCA.
    Tipo de documento:
    Referencia
    Referencia del producto:
    05-844
    Nombre del producto:
    Anti-PLK1 Antibody, clone 35-206

  • Hierarchical requirement of SWI/SNF in retinoblastoma tumor suppressor-mediated repression of Plk1. 15105433

    Plk1 (Polo-like kinase 1) is a critical regulator of cell cycle progression that harbors oncogenic activity and exhibits aberrant expression in multiple tumors. However, the mechanism through which Plk1 expression is regulated has not been extensively studied. Here we demonstrate that Plk1 is a target of the retinoblastoma tumor suppressor (RB) pathway. Activation of RB and related pocket proteins p107/p130 mediate attenuation of Plk1. Conversely, RB loss deregulates the control of Plk1 expression. RB pathway activation resulted in the repression of Plk1 promoter activity, and this action was dependent on the SWI/SNF chromatin remodeling complex. Although SWI/SNF subunits are lost during tumorigenesis and cooperate with RB for transcriptional repression, the mechanism through which SWI/SNF impinges on RB action is unresolved. Therefore, we delineated the requirement of SWI/SNF for three critical facets of Plk1 promoter regulation: transcription factor binding, corepressor binding, and histone modification. We find that E2F4 and pocket protein association with the Plk1 promoter is independent of SWI/SNF. However, these analyses revealed that SWI/SNF is required for histone deacetylation of the Plk1 promoter. The importance of SWI/SNF-dependent histone deacetylation of the Plk1 promoter was evident, because blockade of this event restored Plk1 expression in the presence of active RB. In summary, these data demonstrate that Plk1 is a target of the RB pathway. Moreover, these findings demonstrate a hierarchical role for SWI/SNF in the control of promoter activity through histone modification.
    Tipo de documento:
    Referencia
    Referencia del producto:
    Múltiplo
    Nombre del producto:
    Múltiplo

  • Polo-like kinase 1 is involved in invasion through extracellular matrix. 18056432

    Polo-like kinase 1 (PLK1) has important functions in maintaining genome stability via its role in mitosis. Because PLK1 is up-regulated in many invasive carcinomas, we asked whether it may also play a role in acquisition of invasiveness, a crucial step in transition to malignancy. In a model of metaplastic basal-like breast carcinoma progression, we found that PLK1 expression is necessary but not sufficient to induce invasiveness through laminin-rich extracellular matrix. PLK1 mediates invasion via vimentin and beta1 integrin, both of which are necessary. We observed that PLK1 phosphorylates vimentin on Ser82, which in turn regulates cell surface levels of beta1 integrin. We found PLK1 to be also highly expressed in preinvasive in situ carcinomas of the breast. These results support a role for the involvement of PLK1 in the invasion process and point to this pathway as a potential therapeutic target for preinvasive and invasive breast carcinoma treatment.
    Tipo de documento:
    Referencia
    Referencia del producto:
    MAB1959
    Nombre del producto:
    Anti-Integrin β1 Antibody, clone P5D2

  • Phosphorylation of Plk1 at Ser326 regulates its functions during mitotic progression. 18695677

    Polo-like kinase 1 (Plk1), the best characterized member of the mammalian polo-like kinase family, is well regulated throughout the cell cycle at the protein expression level. Moreover, it is known that Plk1 kinase activity is also regulated at the post-translational level through phosphorylation. However, the upstream kinases of Plk1 have not been identified. Although the involvement of the p38 MAP kinase pathway in cellular responses to stress has been well documented, the role of this pathway in normal cell cycle progression is unclear. Here, we show that phosphorylated p38 and MAP kinase-activated protein kinase 2 (MK2) are colocalized with Plk1 to the spindle poles during prophase and metaphase. Specific depletion of various members of the p38 MAP kinase pathway by the use of RNA interference revealed that the pathway is required for mitotic progression under normal growth conditions. Furthermore, MK2 directly phosphorylates Ser326 of Plk1. Ectopic expression of Plk1-S326A completely blocked cells at mitosis, likely due to the defect of bipolar spindle formation and subsequent activation of the spindle checkpoint. Only Plk1-S326E, but not the Plk1-S326A, efficiently rescued the p38 or MK2-depletion-induced mitotic defects, further solidifying the requirement of S326 phosphorylation during mitotic progression.
    Tipo de documento:
    Referencia
    Referencia del producto:
    Múltiplo
    Nombre del producto:
    Múltiplo