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1. MELK—a conserved kinase: functions, signaling, cancer, and controversy

Author

Ganguly, Ranjit, Mohyeldin, Ahmed, Thiel, Jordyn, Kornblum, Harley I, Beullens, Monique, and Nakano, Ichiro

Subjects
Cancer, Stem Cell Research - Nonembryonic - Human, Stem Cell Research, Stem Cell Research - Nonembryonic - Non-Human, Aetiology, 2.1 Biological and endogenous factors, Maternal embryonic leucine zipper kinase, MELK, Development, Glioblastoma, Glioma-initiating cells, Cancer-initiating cells, Mitotic kinase, Cancer therapeutics, Nursing
Abstract

Maternal embryonic leucine zipper kinase (MELK) is a highly conserved serine/threonine kinase initially found to be expressed in a wide range of early embryonic cellular stages, and as a result has been implicated in embryogenesis and cell cycle control. Recent evidence has identified a broader spectrum of tissue expression pattern for this kinase than previously appreciated. MELK is expressed in several human cancers and stem cell populations. Unique spatial and temporal patterns of expression within these tissues suggest that MELK plays a prominent role in cell cycle control, cell proliferation, apoptosis, cell migration, cell renewal, embryogenesis, oncogenesis, and cancer treatment resistance and recurrence. These findings have important implications for our understanding of development, disease, and cancer therapeutics. Furthermore understanding MELK signaling may elucidate an added dimension of stem cell control.

Published
2015

2. MELK‐Dependent FOXM1 Phosphorylation is Essential for Proliferation of Glioma Stem Cells

Author

Joshi, Kaushal, Banasavadi‐Siddegowda, Yeshavanth, Mo, Xiaokui, Kim, Sung‐Hak, Mao, Ping, Kig, Cenk, Nardini, Diana, Sobol, Robert W, Chow, Lionel ML, Kornblum, Harley I, Waclaw, Ronald, Beullens, Monique, and Nakano, Ichiro

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Biological Sciences, Neurosciences, Brain Cancer, Stem Cell Research - Nonembryonic - Non-Human, Brain Disorders, Genetics, Cancer, Rare Diseases, Stem Cell Research, Stem Cell Research - Nonembryonic - Human, 1.1 Normal biological development and functioning, Underpinning research, Animals, Brain Neoplasms, Cell Cycle Proteins, Cell Proliferation, Cells, Cultured, Dacarbazine, Forkhead Transcription Factors, Glioblastoma, HEK293 Cells, Humans, Mice, Mitosis, Neoplastic Stem Cells, Neural Stem Cells, Peptides, Phosphorylation, Protein Serine-Threonine Kinases, Proto-Oncogene Proteins, Temozolomide, Up-Regulation, Neural stem cell, Cancer stem cell, Glioblastoma stem cell, PLK1, Protein-Serine-Threonine Kinases, Technology, Medical and Health Sciences, Immunology, Biological sciences, Biomedical and clinical sciences
Abstract

Glioblastoma multiforme (GBM) is a life-threatening brain tumor. Accumulating evidence suggests that eradication of glioma stem-like cells (GSCs) in GBM is essential to achieve cure. The transcription factor FOXM1 has recently gained attention as a master regulator of mitotic progression of cancer cells in various organs. Here, we demonstrate that FOXM1 forms a protein complex with the mitotic kinase MELK in GSCs, leading to phosphorylation and activation of FOXM1 in a MELK kinase-dependent manner. This MELK-dependent activation of FOXM1 results in a subsequent increase in mitotic regulatory genes in GSCs. MELK-driven FOXM1 activation is regulated by the binding and subsequent trans-phosphorylation of FOXM1 by another kinase PLK1. Using mouse neural progenitor cells (NPCs), we found that transgenic expression of FOXM1 enhances, while siRNA-mediated gene silencing diminishes neurosphere formation, suggesting that FOXM1 is required for NPC growth. During tumorigenesis, FOXM1 expression sequentially increases as cells progress from NPCs, to pretumorigenic progenitors and GSCs. The antibiotic Siomycin A disrupts MELK-mediated FOXM1 signaling with a greater sensitivity in GSC compared to neural stem cell. Treatment with the first-line chemotherapy agent for GBM, Temozolomide, paradoxically enriches for both FOXM1 (+) and MELK (+) cells in GBM cells, and addition of Siomycin A to Temozolomide treatment in mice harboring GSC-derived intracranial tumors enhances the effects of the latter. Collectively, our data indicate that FOXM1 signaling through its direct interaction with MELK regulates key mitotic genes in GSCs in a PLK1-dependent manner and thus, this protein complex is a potential therapeutic target for GBM.

Published
2013

12. CDK2 Regulates HIV-1 Transcription by Phosphorylation of CDK9 on Serine 90

Author

Breuer Denitra, Kotelkin Alexander, Ammosova Tatiana, Kumari Namita, Ivanov Andrey, Ilatovskiy Andrey V, Beullens Monique, Roane Philip R, Bollen Mathieu, Petukhov Michael G, Kashanchi Fatah, and Nekhai Sergei

Subjects
Immunologic diseases. Allergy, RC581-607
Abstract

Abstract Background HIV-1 transcription is activated by the viral Tat protein that recruits host positive transcription elongation factor-b (P-TEFb) containing CDK9/cyclin T1 to the HIV-1 promoter. P-TEFb in the cells exists as a lower molecular weight CDK9/cyclin T1 dimer and a high molecular weight complex of 7SK RNA, CDK9/cyclin T1, HEXIM1 dimer and several additional proteins. Our previous studies implicated CDK2 in HIV-1 transcription regulation. We also found that inhibition of CDK2 by iron chelators leads to the inhibition of CDK9 activity, suggesting a functional link between CDK2 and CDK9. Here, we investigate whether CDK2 phosphorylates CDK9 and regulates its activity. Results The siRNA-mediated knockdown of CDK2 inhibited CDK9 kinase activity and reduced CDK9 phosphorylation. Stable shRNA-mediated CDK2 knockdown inhibited HIV-1 transcription, but also increased the overall level of 7SK RNA. CDK9 contains a motif (90SPYNR94) that is consensus CDK2 phosphorylation site. CDK9 was phosphorylated on Ser90 by CDK2 in vitro. In cultured cells, CDK9 phosphorylation was reduced when Ser90 was mutated to an Ala. Phosphorylation of CDK9 on Ser90 was also detected with phospho-specific antibodies and it was reduced after the knockdown of CDK2. CDK9 expression decreased in the large complex for the CDK9-S90A mutant and was correlated with a reduced activity and an inhibition of HIV-1 transcription. In contrast, the CDK9-S90D mutant showed a slight decrease in CDK9 expression in both the large and small complexes but induced Tat-dependent HIV-1 transcription. Molecular modeling showed that Ser 90 of CDK9 is located on a flexible loop exposed to solvent, suggesting its availability for phosphorylation. Conclusion Our data indicate that CDK2 phosphorylates CDK9 on Ser 90 and thereby contributes to HIV-1 transcription. The phosphorylation of Ser90 by CDK2 represents a novel mechanism of HIV-1 regulated transcription and provides a new strategy for activation of latent HIV-1 provirus.

Published
2012
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13. Overexpression of PP1-NIPP1 limits the capacity of cells to repair DNA double-strand breaks

Author

Winkler, Claudia, Rouget, Raphael, Wu, Dan, Beullens, Monique, Van Eynde, Aleyde, and Bollen, Mathieu

Subjects
enzymes and coenzymes (carbohydrates), fungi, NIPP1, DNA damage, DNA double-strand breaks, DNA repair, Replication stress, FHA domain, macromolecular substances, biological phenomena, cell phenomena, and immunity, Protein dephosphorylation, PP1
Abstract

The ubiquitously expressed nuclear protein NIPP1 (also known as PPP1R8) recruits phosphoproteins for regulated dephosphorylation by the associated protein phosphatase PP1. To bypass the PP1 titration artifacts seen upon NIPP1 overexpression, we have engineered covalently linked fusions of PP1 and NIPP1, and demonstrate their potential to selectively explore the function of the PP1:NIPP1 holoenzyme. By using inducible stable cell lines, we show that PP1-NIPP1 fusions cause replication stress in a manner that requires both PP1 activity and substrate recruitment via the ForkHead Associated domain of NIPP1. More specifically, PP1-NIPP1 expression resulted in the build up of RNA-DNA hybrids (R-loops), enhanced chromatin compaction and a diminished repair of DNA double-strand breaks (DSBs), culminating in the accumulation of DSBs. These effects were associated with a reduced expression of DNA damage signaling and repair proteins. Our data disclose a key role for dephosphorylation of PP1:NIPP1 substrates in setting the threshold for DNA repair, and indicate that activators of this phosphatase hold therapeutic potential as sensitizers for DNA-damaging agents. ispartof: JOURNAL OF CELL SCIENCE vol:131 issue:13 ispartof: location:England status: published

Published
2018

14. Structure-Guided Exploration of SDS22 Interactions with Protein Phosphatase PP1 and the Splicing Factor BCLAF1

Author

Heroes, Ewald, primary, Van der Hoeven, Gerd, additional, Choy, Meng S., additional, Garcia, Javier del Pino, additional, Ferreira, Mónica, additional, Nys, Mieke, additional, Derua, Rita, additional, Beullens, Monique, additional, Ulens, Chris, additional, Peti, Wolfgang, additional, Van Meervelt, Luc, additional, Page, Rebecca, additional, and Bollen, Mathieu, additional

Published
2019
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16. Correction: MELK-T1, a small-molecule inhibitor of protein kinase MELK, decreases DNA-damage tolerance in proliferating cancer cells

Author

Beke, Lijs, primary, Kig, Cenk, additional, Linders, Joannes T. M., additional, Boens, Shannah, additional, Boeckx, An, additional, van Heerde, Erika, additional, Parade, Marc, additional, De Bondt, An, additional, Van den Wyngaert, Ilse, additional, Bashir, Tarig, additional, Ogata, Souichi, additional, Meerpoel, Lieven, additional, Van Eynde, Aleyde, additional, Johnson, Christopher N., additional, Beullens, Monique, additional, Brehmer, Dirk, additional, and Bollen, Mathieu, additional

Published
2018
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18. Y65C Missense Mutation in the WW Domain of the Golabi-Ito-Hall Syndrome Protein PQBP1 Affects Its Binding Activity and Deregulates Pre-mRNA Splicing

Author

Tapia Victor E., Nicolaescu Emilia, McDonald Caleb B., Musi Valeria, Oka Tsutomu, Inayoshi Yujin, Satteson Adam C., Mazack Virginia, Humbert Jasper, Gaffney Christian J., Beullens Monique, Schwartz Charles E., Landgraf Christiane, Volkmer Rudolf, Pastore A, Farooq Amjad, Bollen Mathieu, Sudol Marius, RI Farooq Amjad/B-5084-2012, Tapia Victor, E., Nicolaescu, Emilia, McDonald Caleb, B., Musi, Valeria, Oka, Tsutomu, Inayoshi, Yujin, Satteson Adam, C., Mazack, Virginia, Humbert, Jasper, Gaffney Christian, J., Beullens, Monique, Schwartz Charles, E., Landgraf, Christiane, Volkmer, Rudolf, Pastore, A, Farooq, Amjad, Bollen, Mathieu, Sudol, Mariu, and RI Farooq, Amjad/B-5084-2012

Subjects
Magnetic Resonance Spectroscopy, Proline, Transcription, Genetic, Protein domain, Mutation, Missense, Calorimetry, Ligands, Biochemistry, WW domain, Splicing factor, Mutant protein, Intellectual Disability, Humans, Missense mutation, Lymphocytes, Nuclear protein, Molecular Biology, Genetics, biology, Circular Dichroism, Alternative splicing, Nuclear Proteins, Molecular Bases of Disease, Cell Biology, Surface Plasmon Resonance, Protein Structure, Tertiary, DNA-Binding Proteins, Alternative Splicing, Mutation, RNA splicing, biology.protein, Carrier Proteins
Abstract

The PQBP1 (polyglutamine tract-binding protein 1) gene encodes a nuclear protein that regulates pre-mRNA splicing and transcription. Mutations in the PQBP1 gene were reported in several X chromosome-linked mental retardation disorders including Golabi-Ito-Hall syndrome. The missense mutation that causes this syndrome is unique among other PQBP1 mutations reported to date because it maps within a functional domain of PQBP1, known as the WW domain. The mutation substitutes tyrosine 65 with cysteine and is located within the conserved core of aromatic amino acids of the domain. We show here that the binding property of the Y65C-mutated WW domain and the full-length mutant protein toward its cognate proline-rich ligands was diminished. Furthermore, in Golabi-Ito-Hall-derived lymphoblasts we showed that the complex between PQBP1-Y65C and WBP11 (WW domain-binding protein 11) splicing factor was compromised. In these cells a substantial decrease in pre-mRNA splicing efficiency was detected. Our study points to the critical role of the WW domain in the function of the PQBP1 protein and provides an insight into the molecular mechanism that underlies the X chromosome-linked mental retardation entities classified globally as Renpenning syndrome.

Published
2010

23. The transcription factor ERG recruits CCR4–NOT to control mRNA decay and mitotic progression

Author

Rambout, Xavier, primary, Detiffe, Cécile, additional, Bruyr, Jonathan, additional, Mariavelle, Emeline, additional, Cherkaoui, Majid, additional, Brohée, Sylvain, additional, Demoitié, Pauline, additional, Lebrun, Marielle, additional, Soin, Romuald, additional, Lesage, Bart, additional, Guedri, Katia, additional, Beullens, Monique, additional, Bollen, Mathieu, additional, Farazi, Thalia A, additional, Kettmann, Richard, additional, Struman, Ingrid, additional, Hill, David E, additional, Vidal, Marc, additional, Kruys, Véronique, additional, Simonis, Nicolas, additional, Twizere, Jean-Claude, additional, and Dequiedt, Franck, additional

Published
2016
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24. Post-translational Control of the Temporal Dynamics of Transcription Factor Activity Regulates Neurogenesis

Author

Quan, Xiao-Jiang, primary, Yuan, Liqun, additional, Tiberi, Luca, additional, Claeys, Annelies, additional, De Geest, Natalie, additional, Yan, Jiekun, additional, van der Kant, Rob, additional, Xie, Wei R., additional, Klisch, Tiemo J., additional, Shymkowitz, Joost, additional, Rousseau, Frederic, additional, Bollen, Mathieu, additional, Beullens, Monique, additional, Zoghbi, Huda Y., additional, Vanderhaeghen, Pierre, additional, and Hassan, Bassem A., additional

Published
2016
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26. MELK-T1, a small-molecule inhibitor of protein kinase MELK, decreases DNA-damage tolerance in proliferating cancer cells

Author

Beke, Lijs, primary, Kig, Cenk, additional, Linders, Joannes T. M., additional, Boens, Shannah, additional, Boeckx, An, additional, van Heerde, Erika, additional, Parade, Marc, additional, De Bondt, An, additional, Van den Wyngaert, Ilse, additional, Bashir, Tarig, additional, Ogata, Souichi, additional, Meerpoel, Lieven, additional, Van Eynde, Aleyde, additional, Johnson, Christopher N., additional, Beullens, Monique, additional, Brehmer, Dirk, additional, and Bollen, Mathieu, additional

Published
2015
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28. Advanced Microscopy Facility, Vienna Biocenter Core Facilities, Dr. Bohr-Gasse 3, 1030 Vienna, Austria.

Author

Winkler, Claudia, Rouget, Raphael, Wu, Dan, Beullens, Monique, Van Eynde, Aleyde, and Bollen, Mathieu

Subjects
NUCLEAR proteins, PHOSPHOPROTEINS, DEPHOSPHORYLATION, PHOSPHATASES, RNA, DNA, BIOCHEMICAL substrates
Abstract

The ubiquitously expressed nuclear protein NIPP1 (also known as PPP1R8) recruits phosphoproteins for regulated dephosphorylation by the associated protein phosphatase PP1. To bypass the PP1 titration artifacts seen upon NIPP1 overexpression, we have engineered covalently linked fusions of PP1 and NIPP1, and demonstrate their potential to selectively explore the function of the PP1:NIPP1 holoenzyme. By using inducible stable cell lines, we show that PP1--NIPP1 fusions cause replication stress in a manner that requires both PP1 activity and substrate recruitment via the ForkHead Associated domain of NIPP1. More specifically, PP1--NIPP1 expression resulted in the build up of RNA--DNA hybrids (R-loops), enhanced chromatin compaction and a diminished repair of DNA double-strand breaks (DSBs), culminating in the accumulation of DSBs. These effects were associated with a reduced expression of DNA damage signaling and repair proteins. Our data disclose a key role for dephosphorylation of PP1:NIPP1 substrates in setting the threshold for DNA repair, and indicate that activators of this phosphatase hold therapeutic potential as sensitizers for DNA-damaging agents. [ABSTRACT FROM AUTHOR]

Published
2018
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33. Abstract 2936: JNJ-47117096, a selective small molecule inhibitor of the MELK oncogene decreases DNA damage tolerance in highly proliferating cancer cells

Author

Beke, Lijs, primary, Linders, Joannes T.m., additional, Kig, Cenk, additional, Boeckx, An, additional, Heerde, Erika van, additional, Wuyts, Dirk, additional, Parade, Marc, additional, Meerpoel, Lieven, additional, Johnson, Chris, additional, Beullens, Monique, additional, Bollen, Mathieu, additional, and Brehmer, Dirk, additional

Published
2014
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34. Protein phosphatase 1 regulates the histone code for long-term memory

Author

Koshibu, Kyoko, Gräff, Johannes, Beullens, Monique, Heitz, Fabrice D., Berchtold, Dominik, Russig, Holger, Farinelli, Mélissa, Bollen, Mathieu, Mansuy, Isabelle M., and University of Zurich

Subjects
10242 Brain Research Institute, 570 Life sciences, biology, 2800 General Neuroscience, 610 Medicine & health
Abstract

Chromatin remodeling through histone posttranslational modifications (PTMs) and DNA methylation has recently been implicated in cognitive functions, but the mechanisms involved in such epigenetic regulation remain poorly understood. Here, we show that protein phosphatase 1 (PP1) is a critical regulator of chromatin remodeling in the mammalian brain that controls histone PTMs and gene transcription associated with long-term memory. Our data show that PP1 is present at the chromatin in brain cells and interacts with enzymes of the epigenetic machinery including HDAC1 (histone deacetylase 1) and histone demethylase JMJD2A (jumonji domain-containing protein 2A). The selective inhibition of the nuclear pool of PP1 in forebrain neurons in transgenic mice is shown to induce several histone PTMs that include not only phosphorylation but also acetylation and methylation. These PTMs are residue-specific and occur at the promoter of genes important for memory formation like CREB (cAMP response element-binding protein) and NF-kappaB (nuclear factor-kappaB). These histone PTMs further co-occur with selective binding of RNA polymerase II and altered gene transcription, and are associated with improved long-term memory for objects and space. Together, these findings reveal a novel mechanism for the epigenetic control of gene transcription and long-term memory in the adult brain that depends on PP1.

Published
2009
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35. Characterization of the condensin component Cnap1 and protein kinase Melk as novel E2F target genes

Author

Verlinden, Lieve, Eelen, Guy, Beullens, Ine, Van Camp, Mark, Van Hummelen, Paul, Engelen, Kristof, Van Hellemont, Ruth, Marchal, Kathleen, De Moor, Bart, Foijer, Floris, Te Riele, Hein, Beullens, Monique, Bollen, Mathieu, Mathieu, Chantal, Bouillon, Roger, and Verstuyf, Annemieke

Subjects
SISTA, Chromosomal Proteins, Non-Histone, Gene Expression Profiling, Research Support, Non-U.S. Gov't, Down-Regulation, Protein-Serine-Threonine Kinases, Cell Line, E2F Transcription Factors, Mice, Calcitriol, Multigene Family, Animals, Cluster Analysis, Humans, Gene Deletion, Oligonucleotide Array Sequence Analysis
Abstract

1,25-Dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) has potent antiproliferative effects characterized by a hampered G(1)/S transition. cDNA microarrays were used to monitor expression of 21,492 genes in MC3T3-E1 mouse osteoblasts at 1, 6, 12, 24, and 36 h after treatment with 1,25(OH)(2)D(3). Statistical analysis revealed a cluster of genes that were strongly down-regulated by 1,25(OH)(2)D(3) and which not only function in cell cycle regulation and DNA replication but also mediate checkpoint control, DNA repair, chromosome modifications, and mitosis. Because many of these genes were shown earlier to be regulated by the transcriptional repressor E2F4, the intergenic regions of these 1,25(OH)(2)D(3)-down-regulated genes were searched for the presence of E2F binding sites. This led to the characterization of two novel E2F target genes, chromosome condensation-related SMC-associated protein 1 (Cnap1) and maternal embryonic leucine zipper kinase (Melk). Transfection studies and site-directed mutagenesis confirmed Cnap1 and Melk to be bona fide E2F targets. Repression of Cnap1 and Melk by 1,25(OH)(2)D(3) was confirmed not only in MC3T3-E1 cells but also in several other bone-unrelated cell types. This down-regulation as well as the antiproliferative effect of 1,25(OH)(2)D(3) depended on the pocket proteins p107 and p130 because 1,25(OH)(2)D(3) failed to repress these E2F target genes and lost its antiproliferative action in p107(-/-);p130(-/-) cells but not in pRb(-/-) cells. ispartof: Journal of Biological Chemistry vol:280 issue:45 pages:37319-37330 ispartof: location:United States status: published

Published
2005

40. A Role for PP1/NIPP1 in Steering Migration of Human Cancer Cells

Author

Martin-Granados, Cristina, primary, Prescott, Alan R., additional, Van Dessel, Nele, additional, Van Eynde, Aleyde, additional, Arocena, Miguel, additional, Klaska, Izabela P., additional, Görnemann, Janina, additional, Beullens, Monique, additional, Bollen, Mathieu, additional, Forrester, John V., additional, and McCaig, Colin D., additional

Published
2012
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45. Synthesis and Characterization of Pseudocantharidins, Novel Phosphatase Modulators That Promote the Inclusion of Exon 7 into the SMN (Survival of Motoneuron) pre-mRNA

Author

Zhang, Zhaiyi, primary, Kelemen, Olga, additional, van Santen, Maria A., additional, Yelton, Sharon M., additional, Wendlandt, Alison E., additional, Sviripa, Vitaliy M., additional, Bollen, Mathieu, additional, Beullens, Monique, additional, Urlaub, Henning, additional, Lührmann, Reinhard, additional, Watt, David S., additional, and Stamm, Stefan, additional

Published
2011
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49. Nuclear Inhibitor of Protein Phosphatase-1 (NIPP1) Directs Protein Phosphatase-1 (PP1) to Dephosphorylate the U2 Small Nuclear Ribonucleoprotein Particle (snRNP) Component, Spliceosome-associated Protein 155 (Sap155)

Author

Tanuma, Nobuhiro, primary, Kim, Sei-Eun, additional, Beullens, Monique, additional, Tsubaki, Yao, additional, Mitsuhashi, Shinya, additional, Nomura, Miyuki, additional, Kawamura, Takeshi, additional, Isono, Kyoichi, additional, Koseki, Haruhiko, additional, Sato, Masami, additional, Bollen, Mathieu, additional, Kikuchi, Kunimi, additional, and Shima, Hiroshi, additional

Published
2008
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