A kinome-wide shRNA screen uncovers vaccinia-related kinase 3 (VRK3) as an essential gene for diffuse intrinsic pontine glioma survival.


:Diffuse intrinsic pontine glioma (or DIPG) are pediatric high-grade gliomas associated with a dismal prognosis. They harbor specific substitution in histone H3 at position K27 that induces major epigenetic dysregulations. Most clinical trials failed so far to increase survival, and radiotherapy remains the most efficient treatment, despite only transient tumor control. We conducted the first lentiviral shRNA dropout screen in newly diagnosed DIPG to generate a cancer-lethal signature as a basis for the development of specific treatments with increased efficacy and reduced side effects compared to existing anticancer therapies. The analysis uncovered 41 DIPG essential genes among the 672 genes of human kinases tested, for which several distinct interfering RNAs impaired cell expansion of three different DIPG stem-cell cultures without deleterious effect on two control neural stem cells. Among them, PLK1, AURKB, CHEK1, EGFR, and GSK3A were previously identified by similar approach in adult GBM indicating common dependencies of these cancer cells and pediatric gliomas. As expected, we observed an enrichment of genes involved in proliferation and cell death processes with a significant number of candidates belonging to PTEN/PI3K/AKT and EGFR pathways already under scrutiny in clinical trials in this disease. We highlighted VRK3, a gene involved especially in cell cycle regulation, DNA repair, and neuronal differentiation, as a non-oncogenic addiction in DIPG. Its repression totally blocked DIPG cell growth in the four cellular models evaluated, and induced cell death in H3.3-K27M cells specifically but not in H3.1-K27M cells, supporting VRK3 as an interesting and promising target in DIPG.






Silva-Evangelista C,Barret E,Ménez V,Merlevede J,Kergrohen T,Saccasyn A,Oberlin E,Puget S,Beccaria K,Grill J,Castel D,Debily MA




Has Abstract


2019-09-01 00:00:00
















  • A novel conditional NPM-ALK-driven model of CD30+ T-cell lymphoma mediated by a translational stop cassette.

    abstract::Targeted expression of transgenes is essential for the accurate representation of human disease in in vivo models. Current approaches to generate conditional transgenic mouse models are cumbersome and not amenable to high-throughput analysis since they require de novo generation and characterization of genetically mod...


    pub_type: 杂志文章


    authors: Shoumariyeh K,Schneider N,Poggio T,Veratti P,Ehrenfeld S,Redhaber DM,Khan R,Pfeifer D,Klingeberg C,Kreutmair S,Rudelius M,Quintanilla-Martinez L,Fend F,Illert AL,Duyster J,Miething C

    更新日期:2020-02-01 00:00:00

  • Discordant regulation of SCL/TAL-1 mRNA and protein during erythroid differentiation.

    abstract::The SCL/TAL1 gene was originally identified by virtue of its rearrangement and transcriptional activation in patients with T cell acute lymphoblastic leukaemia. It encodes a helix-loop-helix transcription factor, is not normally expressed in T cells, but is expressed in erythroid, mast, megakaryocytic and progenitor c...


    pub_type: 杂志文章


    authors: Murrell AM,Bockamp EO,Göttgens B,Chan YS,Cross MA,Heyworth CM,Green AR

    更新日期:1995-07-06 00:00:00

  • Glypican-3 expression is silenced in human breast cancer.

    abstract::Glypican-3 (GPC3) is a membrane-bound heparan sulfate proteoglycan that is mutated in the Simpson-Golabi-Behmel syndrome. This is an X-linked condition characterized by overgrowth, and various visceral and skeletal dysmorphisms. The phenotype of the Simpson-Golabi-Behmel syndrome patients and GPC3-deficient mice, as w...


    pub_type: 杂志文章


    authors: Xiang YY,Ladeda V,Filmus J

    更新日期:2001-11-01 00:00:00

  • TRF2 recruits the Werner syndrome (WRN) exonuclease for processing of telomeric DNA.

    abstract::The cancer-prone and premature aging disease Werner syndrome is due to loss of WRN gene function. Cells lacking WRN demonstrate genomic instability, including telomeric abnormalities and undergo premature senescence, suggesting defects in telomere metabolism. This notion is strongly supported by our finding of physica...


    pub_type: 杂志文章


    authors: Machwe A,Xiao L,Orren DK

    更新日期:2004-01-08 00:00:00

  • TGF-beta receptor type-2 expression in cancer-associated fibroblasts regulates breast cancer cell growth and survival and is a prognostic marker in pre-menopausal breast cancer.

    abstract::Transforming growth factor-beta (TGF-β) is a pleiotropic cytokine with the capability to act as tumour suppressor or tumour promoter depending on the cellular context. TGF-beta receptor type-2 (TGFBR2) is the ligand-binding receptor for all members of the TGF-β family. Data from mouse model experiments demonstrated th...


    pub_type: 杂志文章,随机对照试验


    authors: Busch S,Acar A,Magnusson Y,Gregersson P,Rydén L,Landberg G

    更新日期:2015-01-02 00:00:00

  • Targeting of the protein chaperone, HSP90, by the transformation suppressing agent, radicicol.

    abstract::Radicicol, a macrocyclic anti-fungal antibiotic, has the ability to suppress transformation by diverse oncogenes such as Src, Ras and Mos. Despite this useful property, the mechanism by which radicicol exerts its anti-transformation effects is currently unknown. To understand the transformation-suppressing effects of ...


    pub_type: 杂志文章


    authors: Sharma SV,Agatsuma T,Nakano H

    更新日期:1998-05-01 00:00:00

  • The erythropoietin-receptor pathway modulates survival of cancer cells.

    abstract::Anemia in cancer patients is associated with reduced quality of life and local failure after radiation treatment. However, the use of erythropoietin to correct cancer anemia and to improve radiation efficacy was disappointing. Erythropoietin-receptor signaling mainly acts via activation of STAT 5, but also crossactiva...


    pub_type: 杂志文章


    authors: Pajonk F,Weil A,Sommer A,Suwinski R,Henke M

    更新日期:2004-11-25 00:00:00

  • The putative ovarian tumour marker gene HE4 (WFDC2), is expressed in normal tissues and undergoes complex alternative splicing to yield multiple protein isoforms.

    abstract::The whey acidic protein (WAP) domain is a conserved motif, containing eight cysteines found in a characteristic 4-disulphide core arrangement, that is present in a number of otherwise unrelated proteins. WAP motifs are present in SLPI and elafin, two antiproteinases located on chromosome 20q12-13, in a locus rich in p...


    pub_type: 杂志文章


    authors: Bingle L,Singleton V,Bingle CD

    更新日期:2002-04-18 00:00:00

  • Dissection of the cytoplasmic domains of cytokine receptors involved in STAT and Ras dependent proliferation.

    abstract::Cytokine receptors have different signaling requirements which ultimately lead to various physiological responses. In an effort to precisely characterize the molecular determinants involved in the proliferative response mediated by cytokines, we examine dose-dependent proliferation of the betac (GM-CSF, IL-3, IL-5) an...


    pub_type: 杂志文章


    authors: Piu F,Magnani M,Ader ME

    更新日期:2002-05-16 00:00:00

  • The three transforming regions of SV40 T antigen are required for immortalization of primary mouse embryo fibroblasts.

    abstract::Simian virus 40 (SV40) is a small DNA tumor virus whose early region gene product, large T antigen, is sufficient to immortalize primary rodent cells and transform established rodent cell lines. Three functional domains of large T antigen are required for transformation of the rat embryo fibroblast REF 52 cell line: t...


    pub_type: 杂志文章


    authors: Conzen SD,Cole CN

    更新日期:1995-12-07 00:00:00

  • BCL11B functionally associates with the NuRD complex in T lymphocytes to repress targeted promoter.

    abstract::BCL11 genes play crucial roles in lymphopoiesis and have been associated with hematopoietic malignancies. Specifically, disruption of the BCL11B (B-cell chronic lymphocytic leukemia/lymphoma 11B) locus is linked to T-cell acute lymphoblastic leukemia, and the loss of heterozygosity in mice results in T-cell lymphoma. ...


    pub_type: 杂志文章


    authors: Cismasiu VB,Adamo K,Gecewicz J,Duque J,Lin Q,Avram D

    更新日期:2005-10-13 00:00:00

  • Cell type-specific responses of human cells to inhibition of replication licensing.

    abstract::Replication origins are 'licensed' for a single initiation event by loading Mcm2-7 complexes during late mitosis and G1. Licensing is blocked at other cell cycle stages by the activity of cyclin-dependent kinases and a small protein called geminin. Here, we describe the effects of over-expressing a non-degradable form...


    pub_type: 杂志文章


    authors: Shreeram S,Sparks A,Lane DP,Blow JJ

    更新日期:2002-09-26 00:00:00

  • Use of the two hybrid system to detect the association of the protein-tyrosine-phosphatase, SHPTP2, with another SH2-containing protein, Grb7.

    abstract::SHPTP2 is a ubiquitously-expressed SH2-containing tyrosine phosphatase that is tyrosine phosphorylated in response to activation of various receptor and nonreceptor tyrosine kinases. SHPTP2 associates with the platelet-derived growth factor (PDGF) receptor after ligand stimulation, and binding of SHPTP2 to this recept...


    pub_type: 杂志文章


    authors: Keegan K,Cooper JA

    更新日期:1996-04-04 00:00:00

  • Systems biology analysis of G protein and MAP kinase signaling in yeast.

    abstract::Approximately a third of all drugs act by binding directly to cell surface receptors coupled to G proteins. Other drugs act indirectly on these same pathways, for example, by inhibiting neurotransmitter reuptake or by blocking the inactivation of intracellular second messengers. These drugs have revolutionized the tre...


    pub_type: 杂志文章,评审


    authors: Hao N,Behar M,Elston TC,Dohlman HG

    更新日期:2007-05-14 00:00:00

  • Lessons learned from BRCA1 and BRCA2.

    abstract::BRCA1 and BRCA2 are breast cancer susceptibility genes. Mutations within BRCA1 and BRCA1 are responsible for most familial breast cancer cases. Targeted deletion of Brca1 or Brca2 in mice has revealed an essential function for their encoded products, BRCA1 and BRCA2, in cell proliferation during embryogenesis. Mouse m...


    pub_type: 杂志文章,评审


    authors: Zheng L,Li S,Boyer TG,Lee WH

    更新日期:2000-12-11 00:00:00

  • Caveolin-1 inhibits anchorage-independent growth, anoikis and invasiveness in MCF-7 human breast cancer cells.

    abstract::Caveolin-1 is an essential structural constituent of caveolae that has been implicated in mitogenic signaling and oncogenesis. Caveolin-1 is down-regulated in oncogene-transformed and tumor-derived cells. Antisense suppression of caveolin-1 or expression of a dominant negative form are sufficient for inducing cellular...


    pub_type: 杂志文章


    authors: Fiucci G,Ravid D,Reich R,Liscovitch M

    更新日期:2002-04-04 00:00:00

  • Distinct roles for LINE-1 and HERV-K retroelements in cell proliferation, differentiation and tumor progression.

    abstract::Transformed cells express high levels of non-telomeric reverse-transcriptase (RT) activity of retrotransposon and endogenous retrovirus origin. We previously reported that RT inhibition, either pharmacological or through transient silencing of RT-encoding LINE-1 (L1) elements by RNA interference (RNAi), reduced prolif...


    pub_type: 杂志文章


    authors: Oricchio E,Sciamanna I,Beraldi R,Tolstonog GV,Schumann GG,Spadafora C

    更新日期:2007-06-21 00:00:00

  • Hsp90-inhibitor geldanamycin abrogates G2 arrest in p53-negative leukemia cell lines through the depletion of Chk1.

    abstract::Checkpoint protein Chk1 has been identified as an Hsp90 client. Treatment with 100 nM geldanamycin (GM) for 24 h markedly reduced the Chk1 amount in Jurkat and ML-1 leukemia cell lines. Because Chk1 plays a central role in G2 checkpoint, we added GM to G2-arrested Jurkat and HL-60 cells pretreated with 50 nM doxorubic...


    pub_type: 杂志文章


    authors: Sugimoto K,Sasaki M,Isobe Y,Tsutsui M,Suto H,Ando J,Tamayose K,Ando M,Oshimi K

    更新日期:2008-05-15 00:00:00

  • Differential SKIP expression in PTEN-deficient glioblastoma regulates cellular proliferation and migration.

    abstract::Glioblastoma is the most common and lethal primary malignant brain tumor in adults. The tumor suppressor gene PTEN is deleted, mutated or hypermethylated in more than 60% of glioblastoma cases resulting in hyperactivation of the phosphoinositide 3-kinase pathway, which leads to sustained PI(3,4,5)P3 signaling, and the...


    pub_type: 杂志文章


    authors: Davies EM,Kong AM,Tan A,Gurung R,Sriratana A,Bukczynska PE,Ooms LM,McLean CA,Tiganis T,Mitchell CA

    更新日期:2015-07-01 00:00:00

  • The 26S proteasome system degrades the ERM transcription factor and regulates its transcription-enhancing activity.

    abstract::ERM is a member of the ETS transcription factor family. High levels of the corresponding mRNA are detected in a variety of human breast cancer cell lines, as well as in aggressive human breast tumors. As ERM protein is almost undetectable in these cells, high degradation of this transcription factor has been postulate...


    pub_type: 杂志文章


    authors: Baert JL,Beaudoin C,Monte D,Degerny C,Mauen S,de Launoit Y

    更新日期:2007-01-18 00:00:00

  • The NF-κB subunit c-Rel regulates Bach2 tumour suppressor expression in B-cell lymphoma.

    abstract::The REL gene, encoding the NF-κB subunit c-Rel, is frequently amplified in B-cell lymphoma and functions as a tumour-promoting transcription factor. Here we report the surprising result that c-rel-/- mice display significantly earlier lymphomagenesis in the c-Myc driven, Eμ-Myc model of B-cell lymphoma. c-Rel loss als...


    pub_type: 杂志文章


    authors: Hunter JE,Butterworth JA,Zhao B,Sellier H,Campbell KJ,Thomas HD,Bacon CM,Cockell SJ,Gewurz BE,Perkins ND

    更新日期:2016-06-30 00:00:00

  • PARP1 enhances lung adenocarcinoma metastasis by novel mechanisms independent of DNA repair.

    abstract::The role of poly (ADP-ribose) polymerase 1 (PARP1) in cancer has been extensively studied in the context of DNA repair, leading to clinical trials of PARP1 inhibitors in cancers defective in homologous recombination. However, the DNA repair-independent roles of PARP1 in carcinogenesis and metastasis, particularly in l...


    pub_type: 杂志文章


    authors: Choi EB,Yang AY,Kim SC,Lee J,Choi JK,Choi C,Kim MY

    更新日期:2016-09-01 00:00:00

  • Functional analysis and consequences of Mdm2 E3 ligase inhibition in human tumor cells.

    abstract::Mdm2 is the major negative regulator of p53 tumor-suppressor activity. This oncoprotein is overexpressed in many human tumors that retain the wild-type p53 allele. As such, targeted inhibition of Mdm2 is being considered as a therapeutic anticancer strategy. The N-terminal hydrophobic pocket of Mdm2 binds to p53 and t...


    pub_type: 杂志文章


    authors: Wade M,Li YC,Matani AS,Braun SM,Milanesi F,Rodewald LW,Wahl GM

    更新日期:2012-11-08 00:00:00

  • Antiangiogenic and tumour inhibitory effects of downregulating tumour endothelial FABP4.

    abstract::Fatty acid binding protein 4 (FABP4) is a fatty acid chaperone, which is induced during adipocyte differentiation. Previously we have shown that FABP4 in endothelial cells is induced by the NOTCH1 signalling pathway, the latter of which is involved in mechanisms of resistance to antiangiogenic tumour therapy. Here, we...


    pub_type: 杂志文章


    authors: Harjes U,Bridges E,Gharpure KM,Roxanis I,Sheldon H,Miranda F,Mangala LS,Pradeep S,Lopez-Berestein G,Ahmed A,Fielding B,Sood AK,Harris AL

    更新日期:2017-02-16 00:00:00

  • Calreticulin promotes cell motility and enhances resistance to anoikis through STAT3-CTTN-Akt pathway in esophageal squamous cell carcinoma.

    abstract::We have shown earlier that overexpression of Calreticulin (CRT) contributed to a poor prognosis for patients with esophageal squamous cell carcinoma (ESCC). Here, we have shown an important role of CRT in tumorigenesis through enhancing cell motility and anoikis resistance. SiRNA-mediated knockdown of CRT caused impai...


    pub_type: 杂志文章


    authors: Du XL,Yang H,Liu SG,Luo ML,Hao JJ,Zhang Y,Lin DC,Xu X,Cai Y,Zhan QM,Wang MR

    更新日期:2009-10-22 00:00:00

  • Role of E2F3 expression in modulating cellular proliferation rate in human bladder and prostate cancer cells.

    abstract::Amplification and overexpression of the E2F3 gene at 6p22 in human bladder cancer is associated with increased tumour stage, grade and proliferation index, and in prostate cancer E2F3 overexpression is linked to tumour aggressiveness. We first used small interfering RNA technology to confirm the potential importance o...


    pub_type: 杂志文章


    authors: Olsson AY,Feber A,Edwards S,Te Poele R,Giddings I,Merson S,Cooper CS

    更新日期:2007-02-15 00:00:00

  • TAZ is required for metastatic activity and chemoresistance of breast cancer stem cells.

    abstract::Metastatic growth in breast cancer (BC) has been proposed as an exclusive property of cancer stem cells (CSCs). However, formal proof of their identity as cells of origin of recurrences at distant sites and the molecular events that may contribute to tumor cell dissemination and metastasis development are yet to be el...


    pub_type: 杂志文章


    authors: Bartucci M,Dattilo R,Moriconi C,Pagliuca A,Mottolese M,Federici G,Benedetto AD,Todaro M,Stassi G,Sperati F,Amabile MI,Pilozzi E,Patrizii M,Biffoni M,Maugeri-Saccà M,Piccolo S,De Maria R

    更新日期:2015-02-05 00:00:00

  • Inactivation of hTERT transcription by Tax.

    abstract::Telomerase expression is the hallmark of tumor cells in which this ribonucleoprotein complex preserves chromosome integrity by maintaining telomere length and thereby prevents cell death. However, recent data support a role of the combination of p53 and telomerase inactivation in initiating genetic instability that pr...


    pub_type: 杂志文章


    authors: Gabet AS,Mortreux F,Charneau P,Riou P,Duc-Dodon M,Wu Y,Jeang KT,Wattel E

    更新日期:2003-06-12 00:00:00

  • Expression of the naturally occurring truncated trkB neurotrophin receptor induces outgrowth of filopodia and processes in neuroblastoma cells.

    abstract::We have investigated the effects of the truncated trkB receptor isoform T1 (trkB.T1) by transient transfection into mouse N2a neuroblastoma cells. We observed that expression of trkB.T1 leads to a striking change in cell morphology characterized by outgrowth of filopodia and processes. A similar morphological response...


    pub_type: 杂志文章


    authors: Haapasalo A,Saarelainen T,Moshnyakov M,Arumäe U,Kiema TR,Saarma M,Wong G,Castrén E

    更新日期:1999-02-11 00:00:00

  • Deletion mapping using quantitative real-time PCR identifies two distinct 3p21.3 regions affected in most cervical carcinomas.

    abstract::We report chromosome 3p deletion mapping of 32 cervical carcinoma (CC) biopsies using 26 microsatellite markers located in frequently deleted 3p regions to detect loss of heterozygosity and homozygous loss. In addition, two STS markers (NLJ-003 and NL3-001) located in the 3p21.3 telomeric (3p21.3T) and 3p21.3 centrome...


    pub_type: 杂志文章


    authors: Senchenko V,Liu J,Braga E,Mazurenko N,Loginov W,Seryogin Y,Bazov I,Protopopov A,Kisseljov FL,Kashuba V,Lerman MI,Klein G,Zabarovsky ER

    更新日期:2003-05-15 00:00:00