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12. iPSC-derived neuronal models of PANK2-associated neurodegeneration reveal mitochondrial dysfunction contributing to early disease.

Author

Missirlis, F, Arber, C, Angelova, PR, Wiethoff, S, Tsuchiya, Y, Mazzacuva, F, Preza, E, Bhatia, KP, Mills, K, Gout, I, Abramov, AY, Hardy, J, Duce, JA, Houlden, H, Wray, S, Missirlis, F, Arber, C, Angelova, PR, Wiethoff, S, Tsuchiya, Y, Mazzacuva, F, Preza, E, Bhatia, KP, Mills, K, Gout, I, Abramov, AY, Hardy, J, Duce, JA, Houlden, H, and Wray, S

Abstract

Mutations in PANK2 lead to neurodegeneration with brain iron accumulation. PANK2 has a role in the biosynthesis of coenzyme A (CoA) from dietary vitamin B5, but the neuropathological mechanism and reasons for iron accumulation remain unknown. In this study, atypical patient-derived fibroblasts were reprogrammed into induced pluripotent stem cells (iPSCs) and subsequently differentiated into cortical neuronal cells for studying disease mechanisms in human neurons. We observed no changes in PANK2 expression between control and patient cells, but a reduction in protein levels was apparent in patient cells. CoA homeostasis and cellular iron handling were normal, mitochondrial function was affected; displaying activated NADH-related and inhibited FADH-related respiration, resulting in increased mitochondrial membrane potential. This led to increased reactive oxygen species generation and lipid peroxidation in patient-derived neurons. These data suggest that mitochondrial deficiency is an early feature of the disease process and can be explained by altered NADH/FADH substrate supply to oxidative phosphorylation. Intriguingly, iron chelation appeared to exacerbate the mitochondrial phenotype in both control and patient neuronal cells. This raises caution for the use iron chelation therapy in general when iron accumulation is absent.

Published
2017

13. Application of serex-analysis for identification of human colon cancer antigens

Author

Garifulin O., Kykot V., Gridina N., Kiyamova R., Gout I., and Filonenko V.

Subjects
SEREX-analysis, Allogeneic immunoscreening, Colon cancer
Abstract

Copyright © Experimental Oncology, 2015. Background: Colorectal, lung and breast tumors are the most devastating and frequent malignances in clinical oncology. SEREX-analysis of colon cancer leads to identification of more than hundred antigens which are potential tumor markers. With idea that immunoscreening with pool of allogeneic sera is more productive for antigen isolation, SEREX-analysis was applied to four cases of stages II-IV primary colon tumor and 22 new antigens were isolated. Objective: To characterize 22 primary colon cancer antigens isolated by SEREXtechnique. Materials and Methods: Allogenic screening, real-time PCR analysis. Results: After allogeneic immunoscreening, for 5 of 22 (22%) isolated antigens were confirmed colon cancer restricted serological profile solely positive for 14% of tested colon cancer sera. Through these five antigens, KY-CC-17/β-actin has cytoskeleton function; KY-CC-14/ACTR1A and KY-CC-19/TSGA2 participate in chromosome segregation; KY-CC-12/FKBP4 regulates steroid receptor function and KY-CC-15/PLRG1 is a component of spliceosome complex. For the last four antigens tested were found aberrant mRNA expression in some cases of colon tumor. Conclusion: The exploration of identified antigens may define suitable targets for immunotherapy or diagnostic of colon cancer.

Published
2015

16. Histone acetyltransferases interact with and acetylate p70 ribosomal S6 kinases in vitro and in vivo

Author

Fenton, T. R., Gwalter, J., Ericsson, J., Gout, I. T., Fenton, T. R., Gwalter, J., Ericsson, J., and Gout, I. T.

Abstract

The 70kDa ribosomal protein S6 kinases (S6K1 and S6K2) play important roles in the regulation of protein synthesis, cell growth and survival. S6Ks are activated in response to mitogen stimulation and nutrient sufficiency by the phosphorylation of conserved serine and threonine residues. Here we show for the first time, that in addition to phosphorylation, S6Ks are also targeted by lysine acetylation. Following mitogen stimulation, S6Ks interact with the p300 and p300/CBP-associated factor (PCAF) acetyltransferases. S6Ks can be acetylated by p300 and PCAF in vitro and S6K acetylation is detected in cells expressing p300. Furthermore, it appears that the acetylation sites targeted by p300 lie within the divergent C-terminal regulatory domains of both S6K1 and S6K2. Acetylation of S6K1 and 2 is increased upon the inhibition of class I/II histone deacetylases (HDACs) by trichostatin-A, while the enhancement of S6K1 acetylation by nicotinamide suggests the additional involvement of sirtuin deacetylases in S6K deacetylation. Both expression of p300 and HDAC inhibition cause increases in S6K protein levels, and we have shown that S6K2 is stabilized in cells treated with HDAC inhibitors. The finding that S6Ks are targeted by histone acetyltransferases uncovers a novel mode of crosstalk between mitogenic signalling pathways and the transcriptional machinery and reveals additional complexity in the regulation of S6K function.

Published
2010
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17. Distinct specificity in the recognition of phosphoinositides by the pleckstrin homology domains of dynamin and Bruton's tyrosine kinase

Author

Salim K, Mj, Bottomley, Querfurth E, Marketa Zvelebil, Gout I, Scaife R, Rl, Margolis, Gigg R, Ci, Smith, Pc, Driscoll, Md, Waterfield, and Panayotou G

Subjects
Dynamins, Models, Molecular, Phosphatidylinositol 4,5-Diphosphate, Binding Sites, Magnetic Resonance Spectroscopy, Molecular Sequence Data, Biosensing Techniques, Protein-Tyrosine Kinases, Phosphatidylinositols, GTP Phosphohydrolases, Protein Structure, Tertiary, Enzyme Activation, Phosphatidylinositol Phosphates, Liposomes, Mutagenesis, Site-Directed, Amino Acid Sequence, Sequence Alignment, Protein Binding, Research Article
Abstract

Pleckstrin homology (PH) domains may act as membrane localization modules through specific interactions with phosphoinositide phospholipids. These interactions could represent responses to second messengers, with scope for regulation by soluble inositol polyphosphates. A biosensor-based assay was used here to probe interactions between PH domains and unilamellar liposomes containing different phospholipids and to demonstrate specificity for distinct phosphoinositides. The dynamin PH domain specifically interacted with liposomes containing phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] and, more weakly, with liposomes containing phosphatidylinositol-4-phosphate [PI(4)P]. This correlates with phosphoinositide activation of the dynamin GTPase. The functional GTPase of a dynamin mutant lacking the PH domain, however, cannot be activated by PI(4,5)P2. The phosphoinositide-PH domain interaction can be abolished selectively by point mutations in the putative binding pocket predicted by molecular modelling and NMR spectroscopy. In contrast, the Bruton's tyrosine kinase (Btk)PH domain specifically bound liposomes containing phosphatidylinositol-3,4,5-trisphosphate [PI(3,4,5)P3]: an interaction requiring Arg28, a residue found to be mutated in some X-linked agammaglobulinaemia patients. A rational explanation for these different specificities is proposed through modelling of candidate binding pockets and is supported by NMR spectroscopy.

Published
1996

18. Evidence that the Wiskott-Aldrich syndrome protein may be involved in lymphoid cell signaling pathways

Author

Go, Cory, MacCarthy-Morrogh L, Banin S, Gout I, Pm, Brickell, Rj, Levinsky, Kinnon C, and Ruth Lovering

Subjects
B-Lymphocytes, Binding Sites, Proline, Recombinant Fusion Proteins, Molecular Sequence Data, Gene Expression, Proteins, Cell Differentiation, Burkitt Lymphoma, Peptide Fragments, Wiskott-Aldrich Syndrome, src Homology Domains, src-Family Kinases, Tumor Cells, Cultured, Humans, Amino Acid Sequence, Wiskott-Aldrich Syndrome Protein, Cell Line, Transformed, Protein Binding, Signal Transduction
Abstract

Wiskott-Aldrich syndrome is an X-linked combined immunodeficiency affecting cells of several different hemopoietic lineages. The Wiskott-Aldrich syndrome protein (WASP), which has no homology with any other known protein families, is rich in proline motifs known to contribute to Src homology 3 binding sites. However, its function has not been determined. The Tec family of cytoplasmic tyrosine kinases, which include Btk (the X-linked agammaglobulinemia gene), Itk, and Tec, is thought to be involved in lymphoid cell signaling pathways. In this work, we show binding of WASP to the Src homology 3 domains of Btk, Itk, Tec, Grb2, and phospholipase C-gamma, which suggests a function for WASP in lymphoid cell signaling.

Published
1996

38. A survey of the humoral immune response of cancer patients to a panel of human tumor antigens

Author

Stockert, E, Jäger, E, Chen, Y T, Scanlan, M J, Gout, I, Karbach, J, Arand, Michael; https://orcid.org/0000-0003-2413-3177, Knuth, A, Old, L J, Stockert, E, Jäger, E, Chen, Y T, Scanlan, M J, Gout, I, Karbach, J, Arand, Michael; https://orcid.org/0000-0003-2413-3177, Knuth, A, and Old, L J

Abstract

Evidence is growing for both humoral and cellular immune recognition of human tumor antigens. Antibodies with specificity for antigens initially recognized by cytotoxic T lymphocytes (CTLs), e.g., MAGE and tyrosinase, have been detected in melanoma patient sera, and CTLs with specificity for NY-ESO-1, a cancer-testis (CT) antigen initially identified by autologous antibody, have recently been identified. To establish a screening system for the humoral response to autoimmunogenic tumor antigens, an enzyme-linked immunosorbent assay (ELISA) was developed using recombinant NY-ESO-1, MAGE-1, MAGE-3, SSX2, Melan-A, and tyrosinase proteins. A survey of sera from 234 cancer patients showed antibodies to NY-ESO-1 in 19 patients, to MAGE-1 in 3, to MAGE-3 in 2, and to SSX2 in 1 patient. No reactivity to these antigens was found in sera from 70 normal individuals. The frequency of NY-ESO-1 antibody was 9.4% in melanoma patients and 12.5% in ovarian cancer patients. Comparison of tumor NY-ESO-1 phenotype and NY-ESO-1 antibody response in 62 stage IV melanoma patients showed that all patients with NY-ESO-1(+) antibody had NY-ESO-1(+) tumors, and no patients with NY-ESO-1(-) tumors had NY-ESO-1 antibody. As the proportion of melanomas expressing NY-ESO-1 is 20-40% and only patients with NY-ESO-1(+) tumors have antibody, this would suggest that a high percentage of patients with NY-ESO-1(+) tumors develop an antibody response to NY-ESO-1.

Published
1998

42. Use of yeast two-hybrid system in search of S6K1 and S6K2 binding partners

Author

Zhyvoloup, O. M., primary, Nemazanyy, I. O., additional, Pobigailo, N. V., additional, Panasyuk, G. G., additional, Palchevskyy, S. S., additional, Kuharenko, O. P., additional, Savinska, L. O., additional, Ovcharenko, G. V., additional, Vudmaska, M. I., additional, Gout, I. T., additional, Matsuka, G. Kh., additional, and Filonenko, V. V., additional

Published
2002
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