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77 results on '"Rotblat, Barak"'

51. Cooperation of dominant oncogenes with regulatory germline variants shapes clinical outcomes in childhood cancer

Author

Musa, Julian, primary, Cidre-Aranaz, Florencia, additional, Aynaud, Marie-Ming, additional, Orth, Martin F., additional, Mirabeau, Olivier, additional, Varon, Mor, additional, Grossetête, Sandrine, additional, Surdez, Didier, additional, Ohmura, Shunya, additional, Gerke, Julia S., additional, Marchetto, Aruna, additional, Dallmayer, Marlene, additional, Baldauf, Michaela C., additional, Gartlgruber, Moritz, additional, Westermann, Frank, additional, Stein, Stefanie, additional, Hölting, Tilman L. B., additional, Knott, Maximilian M. L., additional, Sannino, Giuseppina, additional, Li, Jing, additional, Romero-Pérez, Laura, additional, Hartmann, Wolfgang, additional, Dirksen, Uta, additional, Gymrek, Melissa, additional, Anderson, Nathaniel D., additional, Shlien, Adam, additional, Rotblat, Barak, additional, Kirchner, Thomas, additional, Delattre, Olivier, additional, and Grünewald, Thomas G. P., additional

Published
2018
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53. SEC31A mutation affects ER homeostasis, causing a neurological syndrome

Author

Halperin, Daniel, primary, Kadir, Rotem, additional, Perez, Yonatan, additional, Drabkin, Max, additional, Yogev, Yuval, additional, Wormser, Ohad, additional, Berman, Erez M, additional, Eremenko, Ekaterina, additional, Rotblat, Barak, additional, Shorer, Zamir, additional, Gradstein, Libe, additional, Shelef, Ilan, additional, Birk, Ruth, additional, Abdu, Uri, additional, Flusser, Hagit, additional, and Birk, Ohad S, additional

Published
2018
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56. SEC31A mutation affects ER homeostasis, causing a neurological syndrome.

Author

Halperin, Daniel, Kadir, Rotem, Perez, Yonatan, Drabkin, Max, Yogev, Yuval, Wormser, Ohad, Berman, Erez M., Eremenko, Ekaterina, Rotblat, Barak, Shorer, Zamir, Gradstein, Libe, Shelef, Ilan, Birk, Ruth, Abdu, Uri, Flusser, Hagit, and Birk, Ohad S.

Abstract

Background: Consanguineous kindred presented with an autosomal recessive syndrome of intrauterine growth retardation, marked developmental delay, spastic quadriplegia with profound contractures, pseudobulbar palsy with recurrent aspirations, epilepsy, dysmorphism, neurosensory deafness and optic nerve atrophy with no eye fixation. Affected individuals died by the age of 4. Brain MRI demonstrated microcephaly, semilobar holoprosencephaly and agenesis of corpus callosum. We aimed at elucidating the molecular basis of this disease. Methods: Genome-wide linkage analysis combined with whole exome sequencing were performed to identify disease-causing variants. Functional consequences were investigated in fruit flies null mutant for the DrosophilaSEC31A orthologue. SEC31A knockout SH-SY5Y and HEK293T cell-lines were generated using CRISPR/Cas9 and studied through qRT-PCR, immunoblotting and viability assays. Results: Through genetic studies, we identified a disease-associated homozygous nonsense mutation in SEC31A. We demonstrate that SEC31A is ubiquitously expressed, and that the mutation triggers nonsensemediated decay of its transcript, comprising a practical null mutation. Similar to the human disease phenotype, knockdown SEC31A flies had defective brains and early lethality. Moreover, in line with SEC31A encoding one of the two coating layers comprising the Coat protein complex II (COP-II) complex, trafficking newly synthesised proteins from the endoplasmic reticulum (ER) to the Golgi, CRISPR/Cas9-mediated SEC31A null mutant cells demonstrated reduced viability through upregulation of ER-stress pathways. Conclusion: We demonstrate through human and Drosophila genetic and in vitro molecular studies, that a severe neurological syndrome is caused by a null mutation in SEC31A, reducing cell viability through enhanced ER-stress response, in line with SEC31A's role in the COP-II complex. [ABSTRACT FROM AUTHOR]

Published
2019
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60. SEC31Amutation affects ER homeostasis, causing a neurological syndrome

Author

Halperin, Daniel, Kadir, Rotem, Perez, Yonatan, Drabkin, Max, Yogev, Yuval, Wormser, Ohad, Berman, Erez M, Eremenko, Ekaterina, Rotblat, Barak, Shorer, Zamir, Gradstein, Libe, Shelef, Ilan, Birk, Ruth, Abdu, Uri, Flusser, Hagit, and Birk, Ohad S

Abstract

BackgroundConsanguineous kindred presented with an autosomal recessive syndrome of intrauterine growth retardation, marked developmental delay, spastic quadriplegia with profound contractures, pseudobulbar palsy with recurrent aspirations, epilepsy, dysmorphism, neurosensory deafness and optic nerve atrophy with no eye fixation. Affected individuals died by the age of 4. Brain MRI demonstrated microcephaly, semilobar holoprosencephaly and agenesis of corpus callosum. We aimed at elucidating the molecular basis of this disease.MethodsGenome-wide linkage analysis combined with whole exome sequencing were performed to identify disease-causing variants. Functional consequences were investigated in fruit flies null mutant for the Drosophila SEC31Aorthologue. SEC31Aknockout SH-SY5Y and HEK293T cell-lines were generated using CRISPR/Cas9 and studied through qRT-PCR, immunoblotting and viability assays.ResultsThrough genetic studies, we identified a disease-associated homozygous nonsense mutation in SEC31A. We demonstrate that SEC31Ais ubiquitously expressed, and that the mutation triggers nonsense-mediated decay of its transcript, comprising a practical null mutation. Similar to the human disease phenotype, knockdown SEC31Aflies had defective brains and early lethality. Moreover, in line with SEC31Aencoding one of the two coating layers comprising the Coat protein complex II (COP-II) complex, trafficking newly synthesised proteins from the endoplasmic reticulum (ER) to the Golgi, CRISPR/Cas9-mediated SEC31Anull mutant cells demonstrated reduced viability through upregulation of ER-stress pathways.ConclusionWe demonstrate through human and Drosophilagenetic and in vitro molecular studies, that a severe neurological syndrome is caused by a null mutation in SEC31A, reducing cell viability through enhanced ER-stress response, in line with SEC31A’s role in the COP-II complex.

Published
2019
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63. Hace1 controls ROS generation of vertebrate Rac1-dependent NADPH oxidase complexes

Author

Daugaard, Mads, primary, Nitsch, Roberto, additional, Razaghi, Babak, additional, McDonald, Lindsay, additional, Jarrar, Ameer, additional, Torrino, Stéphanie, additional, Castillo-Lluva, Sonia, additional, Rotblat, Barak, additional, Li, Liheng, additional, Malliri, Angeliki, additional, Lemichez, Emmanuel, additional, Mettouchi, Amel, additional, Berman, Jason N., additional, Penninger, Josef M., additional, and Sorensen, Poul H., additional

Published
2013
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76. The Amuvatinib Derivative, N-(2H-1,3-Benzodioxol-5-yl)-4-{thieno[3,2-d]pyrimidin-4-yl}piperazine-1-carboxamide, Inhibits Mitochondria and Kills Tumor Cells under Glucose Starvation.

Author

Marciano, Ran, Ben David, Hila, Akabayov, Barak, and Rotblat, Barak

Subjects
GLUCOSE, STARVATION, SMALL molecules, CELL metabolism, MEMBRANE potential
Abstract

Glucose levels inside solid tumors are low as compared with normal surrounding tissue, forcing tumor cells to reprogram their metabolism to adapt to such low glucose conditions. Unlike normal tissue, tumor cells experience glucose starvation, making the targeting of pathways supporting survival during glucose starvation an interesting therapeutic strategy in oncology. Using high-throughput screening, we previously identified small molecules that selectively kill cells exposed to glucose starvation. One of the identified compounds was the kinase inhibitor amuvatinib. To identify new molecules with potential antineoplastic activity, we procured 12 amuvatinib derivatives and tested their selective toxicity towards glucose-starved tumor cells. One of the amuvatinib derivatives, N-(2H-1,3-benzodioxol-5-yl)-4-{thieno[3,2-d]pyrimidin-4-yl}piperazine-1-carboxamide, termed compound 6, was found to be efficacious in tumor cells experiencing glucose starvation. In line with the known dependence of glucose-starved cells on the mitochondria, compound 6 inhibits mitochondrial membrane potential. These findings support the concept that tumor cells are dependent on mitochondria under glucose starvation, and bring forth compound 6 as a new molecule with potential antitumor activity for the treatment of glucose-starved tumors. [ABSTRACT FROM AUTHOR]

Published
2020
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77. [Surviving nutrient deprivation by restraining translation elongation: biological function of the eEF2 kinase].

Author

Leprivier G, Rotblat B, Delattre O, and Sorensen PH

Subjects
AMP-Activated Protein Kinases physiology, Animals, Caenorhabditis elegans genetics, Caenorhabditis elegans physiology, Elongation Factor 2 Kinase genetics, Gene Expression, Humans, Neoplasms pathology, Peptide Chain Elongation, Translational, TOR Serine-Threonine Kinases physiology, Cell Survival physiology, Elongation Factor 2 Kinase physiology
Published
2013
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