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Jochem M G Evers, Roman A Laskowski, Marta Bertolli, Jill Clayton-Smith, Charu Deshpande, Jacqueline Eason, Frances Elmslie, Frances Flinter, Carol Gardiner, Jane A Hurst, Helen Kingston, Usha Kini, Anne K Lampe, Derek Lim, Alison Male, Swati Naik, Michael J Parker, Sue Price, Leema Robert, Ajoy Sarkar, Volker Straub, Geoff Woods, Janet M Thornton, Caroline F Wright
Haploinsufficiency in DYRK1A is associated with a recognizable developmental syndrome, though the mechanism of action of pathogenic missense mutations is currently unclear. Here we present 19 de novo mutations in this gene, including five missense mutations, identified by the Deciphering Developmental Disorder study. Protein structural analysis reveals that the missense mutations are either close to the ATP or peptide binding-sites within the kinase domain, or are important for protein stability, suggesting they lead to a loss of the protein's function mechanism...
January 4, 2017: Human Molecular Genetics
Meropi Sklepari, Nikolaos Lougiakis, Athanasios Papastathopoulos, Nicole Pouli, Panagiotis Marakos, Vassilios Myrianthopoulos, Thomas Robert, Stéphane Bach, Emmanuel Mikros, Sandrine Ruchaud
A series of new pyrazolo[3,4-c]pyridines bearing various 1, 3, 5 or 1, 3, 7 pattern substitutions, were designed and synthesized. Some of them showed interesting inhibitory activity mainly against glycogen synthase kinase 3 (GSK3)α/β as well as against cdc2-like kinases 1 (CLK1) and dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), with good selectivity and remarkable structure-activity relationships (SARs), without being cytotoxic. Molecular simulations in correlation with biological data revealed the importance of the existence of N1-H as well as the absence of a bulky 7-substituent...
2017: Chemical & Pharmaceutical Bulletin
James MacDonald, Yudith Ramos-Valdes, Piru Perampalam, Larisa Litovchick, Gabriel E DiMattia, Frederick A Dick
: Epithelial ovarian cancer (EOC) generates multicellular aggregates called spheroids that detach from the primary tumor and disseminate through ascites. Spheroids possess a number of characteristics of tumor dormancy including withdrawal from the cell cycle and resistance to chemotherapeutics. This report systematically analyzes the effects of RNAi depletion of 21 genes that are known to contribute to negative regulation of the cell cycle in 10 ovarian cancer cell lines. Interestingly, spheroid cell viability was compromised by loss of some Cyclin Dependent Kinase Inhibitors such as p57Kip2, as well as Dyrk1A, Lin52, and E2F5 in most cell lines tested...
December 28, 2016: Molecular Cancer Research: MCR
Vanja Dakic, Renata de Moraes Maciel, Hannah Drummond, Juliana M Nascimento, Pablo Trindade, Stevens K Rehen
Harmine is the β-carboline alkaloid with the highest concentration in the psychotropic plant decoction Ayahuasca. In rodents, classical antidepressants reverse the symptoms of depression by stimulating neuronal proliferation. It has been shown that Ayahuasca presents antidepressant effects in patients with depressive disorder. In the present study, we investigated the effects of harmine in cell cultures containing human neural progenitor cells (hNPCs, 97% nestin-positive) derived from pluripotent stem cells...
2016: PeerJ
Qiang Liu, Yu Tang, Long Chen, Na Liu, Fangfang Lang, Heng Liu, Pin Wang, Xiulian Sun
DYRK1A, located on the Down syndrome (DS) critical region of chromosome 21, was found to be overexpressed in brains of DS and Alzheimer's disease individuals. DYRK1A was considered to play important roles in the pathogenesis of DS and Alzheimer's disease; however, the degradation mechanism of DYRK1A was still unclear. In this study, we found that DYRK1A was degraded through the ubiquitin-proteasome pathway in HEK293 cells. The N terminus of DYRK1A that was highly unstable in HEK293 cells contributed to proteolysis of DYRK1A...
December 16, 2016: Journal of Biological Chemistry
Aneesha Radhakrishnan, Vishalakshi Nanjappa, Remya Raja, Gajanan Sathe, Vinuth N Puttamallesh, Ankit P Jain, Sneha M Pinto, Sai A Balaji, Sandip Chavan, Nandini A Sahasrabuddhe, Premendu P Mathur, Mahesh M Kumar, T S Keshava Prasad, Vani Santosh, Geethanjali Sukumar, Joseph A Califano, Annapoorni Rangarajan, David Sidransky, Akhilesh Pandey, Harsha Gowda, Aditi Chatterjee
Despite advances in clinical management, 5-year survival rate in patients with late-stage head and neck squamous cell carcinoma (HNSCC) has not improved significantly over the past decade. Targeted therapies have emerged as one of the most promising approaches to treat several malignancies. Though tyrosine phosphorylation accounts for a minority of total phosphorylation, it is critical for activation of signaling pathways and plays a significant role in driving cancers. To identify activated tyrosine kinase signaling pathways in HNSCC, we compared the phosphotyrosine profiles of a panel of HNSCC cell lines to a normal oral keratinocyte cell line...
October 31, 2016: Scientific Reports
E Sacide Çağlayan
Dual-specificity thyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a strong therapeutic target to ameliorate cognitive functions of Down Syndrome (DS). Genetic normalization of Dyrk1a is sufficient to normalize early cortical developmental phenotypes in DS mouse models. Gyrencephalic human neocortical development is more complex than that in lissencephalic mice; hence, cerebral organoids (COs) can be used to model early neurodevelopmental defects of DS. Single copy DYRK1A knockout COs (scDYRK1AKO-COs) can be generated from manipulated DS derived (DS-) induced pluripotent stem cells (iPSCs) and genetic normalization of DYRK1A is expected to result in corrected neurodevelopmental phenotypes that can be reminiscent of normal COs...
December 2016: Cell Biology International
Ulli Rothweiler, Wenche Stensen, Bjørn Olav Brandsdal, Johan Isaksson, Frederick Alan Leeson, Richard Alan Engh, John S Mjøen Svendsen
DYRK1A has emerged as a potential target for therapies of Alzheimer's disease using small molecules. On the basis of the observation of selective DYRK1A inhibition by firefly d-luciferin, we have explored static and dynamic structural properties of fragment sized variants of the benzothiazole scaffold with respect to DYRK1A using X-ray crystallography and NMR techniques. The compounds have excellent ligand efficiencies and show a remarkable diversity of binding modes in dynamic equilibrium. Binding geometries are determined in part by interactions often considered "weak", including "orthogonal multipolar" types represented by, for example, F-CO, sulfur-aromatic, and halogen-aromatic interactions, together with hydrogen bonds that are modulated by variation of electron withdrawing groups...
November 10, 2016: Journal of Medicinal Chemistry
Lyamin Z Bendjeddou, Nadège Loaëc, Benoît Villiers, Eric Prina, Gerald F Späth, Hervé Galons, Laurent Meijer, Nassima Oumata
3,6-Disubstituted imidazo[1,2-b]pyridazine derivatives were synthesized to identify new inhibitors of various eukaryotic kinases, including mammalian and protozoan kinases. Among the imidazo[1,2-b]pyridazines tested as kinase inhibitors, several derivatives were selective for DYRKs and CLKs, with IC50 < 100 nM. The characterization of the kinome of several parasites, such as Plasmodium and Leishmania, has pointed out profound divergences between protein kinases of the parasites and those of the host. This led us to investigate the activities of the prepared compounds against 11 parasitic kinases...
January 5, 2017: European Journal of Medicinal Chemistry
Luis G Rabaneda, Noelia Geribaldi-Doldán, Maribel Murillo-Carretero, Manuel Carrasco, José M Martínez-Salas, Cristina Verástegui, Carmen Castro
Hyperhomocysteinemia reduces neurogenesis in the adult mouse brain. Homocysteine (Hcy) inhibits postnatal neural progenitor cell (NPC) proliferation by specifically impairing the fibroblast growth factor receptor (FGFR)-Erk1/2-cyclin E signaling pathway. We demonstrate herein that the inhibition of FGFR-dependent NPC proliferation induced by Hcy is mediated by its capacity to alter the cellular methylation potential. Our results show that this alteration modified the expression pattern and activity of Sprouty2 (Spry2), a negative regulator of the above mentioned pathway...
December 2016: Biochimica et Biophysica Acta
Christophe Labrière, Olivier Lozach, Mélina Blairvacq, Laurent Meijer, Catherine Guillou
Starting from a known compound, identified as the first inhibitor of the kinesin MKLP-2 and named Paprotrain, we have investigated its reactivity to produce through photochemistry a potent nanomolar inhibitor of the kinase DYRK1A. Using similar and different chemical pathways, we have designed several families of compounds that have been screened on a panel of five protein kinases: CK1δ/ε, CDK5/p25, GSK3α/β, DYRK1A and CLK1, all involved in neurodegenerative disorders such as Alzheimer's disease. We have identified a first group of multi-targeted compounds, a second group of dual inhibitors of DYRK1A & CLK1 and a last group of selective inhibitors of CLK1...
November 29, 2016: European Journal of Medicinal Chemistry
Giada Zurlo, Jianping Guo, Mamoru Takada, Wenyi Wei, Qing Zhang
Protein hydroxylation is a post-translational modification catalyzed by 2-oxoglutarate-dependent dioxygenases. The hydroxylation modification can take place on various amino acids, including but not limited to proline, lysine, asparagine, aspartate and histidine. A classical example of this modification is hypoxia inducible factor alpha (HIF-α) prolyl hydroxylation, which affects HIF-α protein stability via the Von-Hippel Lindau (VHL) tumor suppressor pathway, a Cullin 2-based E3 ligase adaptor protein frequently mutated in kidney cancer...
December 2016: Biochimica et Biophysica Acta
Kristie I Aamodt, Radhika Aramandla, Judy J Brown, Nathalie Fiaschi-Taesch, Peng Wang, Andrew F Stewart, Marcela Brissova, Alvin C Powers
Numerous compounds stimulate rodent β-cell proliferation; however, translating these findings to human β-cells remains a challenge. To examine human β-cell proliferation in response to such compounds, we developed a medium-throughput in vitro method of quantifying adult human β-cell proliferation markers. This method is based on high-content imaging of dispersed islet cells seeded in 384-well plates and automated cell counting that identifies fluorescently labeled β-cells with high specificity using both nuclear and cytoplasmic markers...
November 1, 2016: American Journal of Physiology. Endocrinology and Metabolism
J Shirakawa, R N Kulkarni
β-Cell dysfunction in type 1 and type 2 diabetes is accompanied by a progressive loss of β-cells, and an understanding of the cellular mechanism(s) that regulate β-cell mass will enable approaches to enhance hormone secretion. It is becoming increasingly recognized that enhancement of human β-cell proliferation is one potential approach to restore β-cell mass to prevent and/or cure type 1 and type 2 diabetes. While several reports describe the factor(s) that enhance β-cell replication in animal models or cell lines, promoting effective human β-cell proliferation continues to be a challenge in the field...
September 2016: Diabetes, Obesity & Metabolism
Liu Yang, Sayantanee Paul, Kenneth G Trieu, Lucas G Dent, Francesca Froldi, Marta Forés, Kaitlyn Webster, Kellee R Siegfried, Shu Kondo, Kieran Harvey, Louise Cheng, Gerardo Jiménez, Stanislav Y Shvartsman, Alexey Veraksa
The transcriptional repressor Capicua (Cic) controls tissue patterning and restricts organ growth, and has been recently implicated in several cancers. Cic has emerged as a primary sensor of signaling downstream of the receptor tyrosine kinase (RTK)/extracellular signal-regulated kinase (ERK) pathway, but how Cic activity is regulated in different cellular contexts remains poorly understood. We found that the kinase Minibrain (Mnb, ortholog of mammalian DYRK1A), acting through the adaptor protein Wings apart (Wap), physically interacts with and phosphorylates the Cic protein...
September 20, 2016: Proceedings of the National Academy of Sciences of the United States of America
Samantha D McElyea, John M Starbuck, Danika M Tumbleson-Brink, Emily Harrington, Joshua D Blazek, Ahmed Ghoneima, Katherine Kula, Randall J Roper
Trisomy 21 (Ts21) affects craniofacial precursors in individuals with Down syndrome (DS). The resultant craniofacial features in all individuals with Ts21 may significantly affect breathing, eating and speaking. Using mouse models of DS, we have traced the origin of DS-associated craniofacial abnormalities to deficiencies in neural crest cell (NCC) craniofacial precursors early in development. Hypothetically, three copies of Dyrk1a (dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A), a trisomic gene found in most humans with DS and mouse models of DS, may significantly affect craniofacial structure...
September 5, 2016: Human Molecular Genetics
Jongchan Kim, Ashley N Siverly, Dahu Chen, Min Wang, Yuan Yuan, Yumeng Wang, Hyemin Lee, Jinsong Zhang, William J Muller, Han Liang, Boyi Gan, Xianbin Yang, Yutong Sun, M James You, Li Ma
The invasive and metastatic properties of many human tumors have been associated with upregulation of the miRNA miR-10b, but its functional contributions in this setting have not been fully unraveled. Here, we report the generation of miR-10b-deficient mice, in which miR-10b is shown to be largely dispensable for normal development but critical to tumorigenesis. Loss of miR-10b delays oncogene-induced mammary tumorigenesis and suppresses epithelial-mesenchymal transition, intravasation, and metastasis in a mouse model of metastatic breast cancer...
November 1, 2016: Cancer Research
L J Kay, T K Smulders-Srinivasan, M Soundararajan
The dual-specificity tyrosine (Y) phosphorylation-regulated kinase DYRK1A, also known as Down syndrome (DS) kinase, is a dosage-dependent signaling kinase that was originally shown to be highly expressed in DS patients as a consequence of trisomy 21. Although this was evident some time ago, it is only in recent investigations that the molecular roles of DYRK1A in a wide range of cellular processes are becoming increasingly apparent. Since initial knowledge on DYRK1A became evident through minibrain mnb, the Drosophila homolog of DYRK1A, this review will first summarize the scientific reports on minibrain and further expand on the well-established neuronal functions of mammalian and human DYRK1A...
2016: Advances in Protein Chemistry and Structural Biology
Junhua Geng, Liping Wang, Joo Yeun Lee, Chun-Kan Chen, Karen T Chang
UNLABELLED: The rapid replenishment of synaptic vesicles through endocytosis is crucial for sustaining synaptic transmission during intense neuronal activity. Synaptojanin (Synj), a phosphoinositide phosphatase, is known to play an important role in vesicle recycling by promoting the uncoating of clathrin following synaptic vesicle uptake. Synj has been shown to be a substrate of the minibrain (Mnb) kinase, a fly homolog of the dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A); however, the functional impacts of Synj phosphorylation by Mnb are not well understood...
August 24, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Luan Cen, Yousheng Xiao, Lei Wei, Mingshu Mo, Xiang Chen, Shaomin Li, Xingling Yang, Qinghui Huang, Shaogang Qu, Zhong Pei, Pingyi Xu
α-Synuclein plays important roles in the development of Parkinson's disease (PD) pathologies. The dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) has a wide range of phosphorylation targets including α-synuclein. Posphorylated α-synuclein is more neurotoxic to dopamine (DA) neurons, but little is known about the genetic variation of DYRK1A in patients with PD. The present investigation aimed to explore the possible association of DYRK1A gene with PD in Chinese Han population. A total of 268 PD patients and 268 healthy-matched individuals in Chinese Han population were enrolled...
October 6, 2016: Neuroscience Letters
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