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91 results on '"Gurova K"'

1. Prognostic value of histone chaperone FACT subunits expression in breast cancer

Author: Attwood K, Fleyshman D, Prendergast L, Paszkiewicz G, Omilian AR, Bshara W, and Gurova K
Subjects: SSRP1, SPT16, breast cancer, predictive marker, prognosis, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Kristopher Attwood,1 Daria Fleyshman,2 Laura Prendergast,2 Geraldine Paszkiewicz,2 Angela R Omilian,3 Wiam Bshara,3 Katerina Gurova2 1Department of Biostatistics and Bioinformatics, 2Department of Cell Stress Biology, 3Department of Pathology, Roswell Park Cancer Institute, Buffalo, NY, USA Abstract: Understanding the underlying reasons for tumor aggressiveness, such as why some tumors grow slowly and locally, while others rapidly progress to a lethal metastatic disease, is still limited. This is especially critical in breast cancer (BrCa) due to its high prevalence and also due to the possibility that it can be detected early. Several oncogenes and tumor suppressors have been identified and are used in the prognosis and treatment of BrCa. However, even with these markers, the outcome within BrCa subtypes is highly variable. Chromatin organization has long been acknowledged as a factor that plays an important role in tumor progression, but molecular mechanisms defining chromatin dynamics are largely missing. We have recently found that histone chaperone FACT (facilitates chromatin transcription) is overexpressed in ~18–20% of BrCa cases. FACT is elevated upon transformation of mammary epithelial cells and is essential for viability of tumor cells. BrCa cells with high FACT have a more aggressive transcriptional program than those with low FACT cells. Based on this we propose that FACT may be a marker of aggressive BrCa. In this study, we aimed to comprehensively characterize the pattern of FACT expression in BrCa in relation to other molecular and clinical prognostic markers. We developed and tested an assay for the detection and quantitation of protein levels of both FACT subunits, SSRP1, and SPT16, in clinical samples. We compared the value of mRNA and protein as potential markers of disease aggressiveness using a large cohort of patients (n=1092). We demonstrated that only SSRP1 immunohistochemical staining is a reliable indicator of FACT levels in tumor samples. High SSRP1 correlated with known markers of poor prognosis, such as negative hormone receptor status, presence of Her2, high-grade tumors, and tumors of later clinical stage. At the same time, no strong correlation between SSRP1 expression and survival was detected when all samples were analyzed together. Clear trend toward longer survival of patients with low or no SSRP1 expression in tumor samples was seen in several subgroups of patients, and most importantly significant association of high SSRP1 expression with shorter disease-free survival was detected in patients with early-stage and low-grade BrCa, the category of patients with the highest demand in predictive marker of disease progression. Keywords: SSRP1, SPT16, breast cancer, predictive marker, prognosis
Published: 2017

2. Effects of CSFS and their Combinations with Chemotherapeutic Agents (CH) on Leukemic Blasts (LB) in Children (MTT-Assay)

Author: Litvinova, E., Gurova, K., Chimishkian, K., Mentkevich, G., Kaspers, G. J. L., editor, Pieters, R., editor, and Veerman, A. J. P., editor
Published: 1999
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3. 9-Aminoacridine-based anticancer drugs target the PI3K/AKT/mTOR, NF-κB and p53 pathways

Author: Guo, C, Gasparian, A V, Zhuang, Z, Bosykh, D A, Komar, A A, Gudkov, A V, and Gurova, K V
Published: 2009
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4. Mycoplasma infection suppresses p53, activates NF-κB and cooperates with oncogenic Ras in rodent fibroblast transformation

Author: Logunov, D Y, Scheblyakov, D V, Zubkova, O V, Shmarov, M M, Rakovskaya, I V, Gurova, K V, Tararova, N D, Burdelya, L G, Naroditsky, B S, Ginzburg, A L, and Gudkov, A V
Published: 2008
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5. Dual targeting of the epigenome via FACT complex and histone deacetylase is a potent treatment strategy for DIPG

Author: Ehteda, A, Simon, S, Franshaw, L, Giorgi, FM, Liu, J, Joshi, S, Rouaen, JRC, Pang, CNI, Pandher, R, Mayoh, C, Tang, Y, Khan, A, Ung, C, Tolhurst, O, Kankean, A, Hayden, E, Lehmann, R, Shen, S, Gopalakrishnan, A, Trebilcock, P, Gurova, K, Gudkov, AV, Norris, MD, Haber, M, Vittorio, O, Tsoli, M, Ziegler, DS, Ehteda, A, Simon, S, Franshaw, L, Giorgi, FM, Liu, J, Joshi, S, Rouaen, JRC, Pang, CNI, Pandher, R, Mayoh, C, Tang, Y, Khan, A, Ung, C, Tolhurst, O, Kankean, A, Hayden, E, Lehmann, R, Shen, S, Gopalakrishnan, A, Trebilcock, P, Gurova, K, Gudkov, AV, Norris, MD, Haber, M, Vittorio, O, Tsoli, M, and Ziegler, DS
Abstract: Diffuse intrinsic pontine glioma (DIPG) is an aggressive and incurable childhood brain tumor for which new treatments are needed. CBL0137 is an anti-cancer compound developed from quinacrine that targets facilitates chromatin transcription (FACT), a chromatin remodeling complex involved in transcription, replication, and DNA repair. We show that CBL0137 displays profound cytotoxic activity against a panel of patient-derived DIPG cultures by restoring tumor suppressor TP53 and Rb activity. Moreover, in an orthotopic model of DIPG, treatment with CBL0137 significantly extends animal survival. The FACT subunit SPT16 is found to directly interact with H3.3K27M, and treatment with CBL0137 restores both histone H3 acetylation and trimethylation. Combined treatment of CBL0137 with the histone deacetylase inhibitor panobinostat leads to inhibition of the Rb/E2F1 pathway and induction of apoptosis. The combination of CBL0137 and panobinostat significantly prolongs the survival of mice bearing DIPG orthografts, suggesting a potential treatment strategy for DIPG.
Published: 2021

6. Targeted disruption of the mouse ing1 locus results in reduced body size, hypersensitivity to radiation and elevated incidence of lymphomas

Author: Kichina, J V, Zeremski, M, Aris, L, Gurova, K V, Walker, E, Franks, R, Nikitin, A Y, Kiyokawa, H, and Gudkov, A V
Published: 2006
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7. High expression of shMDG1 gene is associated with low metastatic potential of tumor cells

Author: Isachenko, N, Dyakova, N, Aushev, V, Chepurnych, T, Gurova, K, and Tatosyan, A
Published: 2006
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8. Effects of CSFS and their Combinations with Chemotherapeutic Agents (CH) on Leukemic Blasts (LB) in Children (MTT-Assay)

Author: Litvinova, E., primary, Gurova, K., additional, Chimishkian, K., additional, and Mentkevich, G., additional
Published: 1999
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9. Potent antileukemic activity of curaxin CBL0137 against MLL-rearranged leukemia

Author: Somers, K, Kosciolek, A, Bongers, A, El-Ayoubi, A, Karsa, M, Mayoh, C, Wadham, C, Middlemiss, S, Neznanov, N, Kees, UR, Lock, RB, Gudkov, A, Sutton, R, Gurova, K, Haber, M, Norris, MD, Henderson, MJ, Somers, K, Kosciolek, A, Bongers, A, El-Ayoubi, A, Karsa, M, Mayoh, C, Wadham, C, Middlemiss, S, Neznanov, N, Kees, UR, Lock, RB, Gudkov, A, Sutton, R, Gurova, K, Haber, M, Norris, MD, and Henderson, MJ
Abstract: © 2019 UICC Around 10% of acute leukemias harbor a rearrangement of the MLL/KMT2A gene, and the presence of this translocation results in a highly aggressive, therapy-resistant leukemia subtype with survival rates below 50%. There is a high unmet need to identify safer and more potent therapies for MLL-rearranged (MLL-r) leukemia that can be combined with established chemotherapeutics to decrease treatment-related toxicities. The curaxin, CBL0137, has demonstrated nongenotoxic anticancer and chemopotentiating effects in a number of preclinical cancer models and is currently in adult Phase I clinical trials for solid tumors and hematological malignancies. The aim of our study was to investigate whether CBL0137 has potential as a therapeutic and chemopotentiating compound in MLL-r leukemia through a comprehensive analysis of its efficacy in preclinical models of the disease. CBL0137 decreased the viability of a panel of MLL-r leukemia cell lines (n = 12) and xenograft cells derived from patients with MLL-r acute lymphoblastic leukemia (ALL, n = 3) in vitro with submicromolar IC50s. The small molecule drug was well-tolerated in vivo and significantly reduced leukemia burden in a subcutaneous MV4;11 MLL-r acute myeloid leukemia model and in patient-derived xenograft models of MLL-r ALL (n = 5). The in vivo efficacy of standard of care drugs used in remission induction for pediatric ALL was also potentiated by CBL0137. CBL0137 exerted its anticancer effect by trapping Facilitator of Chromatin Transcription (FACT) into chromatin, activating the p53 pathway and inducing an Interferon response. Our findings support further preclinical evaluation of CBL0137 as a new approach for the treatment of MLL-r leukemia.
Published: 2019

10. Activation of interferon-α signaling by resveratrol, genistein and quercetin

Author: Vlasova, O. A., primary, Borunova, A. A., additional, Safina, A., additional, Smetanina, I. V., additional, Lesovaya, E. A., additional, Belitsky, G. A., additional, Zabotina, T. N., additional, Gurova, K., additional, Kirsanov, K. I., additional, and Yakubovskaya, M. G., additional
Published: 2019
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11. Influence of DNA-binding compounds with cancer preventive activity on the mechanisms of gene expression regulation

Author: Kirsanov, K. I., primary, Vlasova, O. A., additional, Fetisov, T. I., additional, Zenkov, R. G., additional, Lesovaya, E. A., additional, Belitsky, G. A., additional, Gurova, K., additional, and Yakubovskaya, M. G., additional
Published: 2019
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12. ENTERPRISE UNIVERSITY: INTEGRATION OF EDUCATION, SCIENCE, BUSINESS

Author: Voronkova, T., primary and Gurova, K., additional
Published: 2018
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13. PO-464 Influence of natural DNA-binding compounds with cancer preventive activity on chromatin structure

Author: Vlasova, O., primary, Maksimova, V., additional, Safina, A., additional, Belitsky, G., additional, Gurova, K., additional, Kirsanov, K., additional, and Yakubovskaya, M., additional
Published: 2018
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14. PO-459 Systemic anti-inflammatory effect of a new anticancer cyclic peptide ALOS4

Author: Nesher, E., primary, Pinhasov, A., additional, Becker, M., additional, Cohen-Harazi, R., additional, Yakobovich, S., additional, Gitlin, I., additional, Leonova, K., additional, Gurova, K., additional, Gudkov, A., additional, and Koman, I., additional
Published: 2018
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15. PO-158 Induction of interferon signalling by natural DNA-binding compounds with cancer preventive activity

Author: Vlasova, O., primary, Safina, A., additional, Lesovaya, E., additional, Fetisov, T., additional, Belitsky, G., additional, Gurova, K., additional, Yakubovskaya, M., additional, and Kirsanov, K., additional
Published: 2018
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16. Thermal study of some sulphosuccinates

Author: Petrova, L. and Gurova, K.
Published: 1989
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17. Derivatographic investigation of glass fibre adsorbents based on bentone clay

Author: Ljubchev, L., Obretenov, Ts., Gogov, D., and Gurova, K.
Published: 1984
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18. Antitumor effect of the curaxin CBL0137 on the models of colon cancer

Author: Fetisov, T. I., primary, Tilova, L. R., additional, Lesovaya, E. A., additional, Antoshina, E. E., additional, Gor’kova, T. G., additional, Trukhanova, L. S., additional, Morozova, O. V., additional, Shipaeva, E. V., additional, Ivanov, R. V., additional, Purmal, A. A., additional, Belitskiy, G. A., additional, Yakubovskaya, M. G., additional, Gudkov, A. V., additional, Gurova, K. V., additional, and Kirsanov, K. I., additional
Published: 2016
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19. CBL0137, a novel NFkB suppressor and p53 activator, is highly effective in pre-clinical models of neuroblastoma

Author: Haber, M., Murray, J., Gamble, L., Carnegie-Clark, A., Webber, H., Ruhle, M., Carter, D., Oberthur, A., Fischer, M., Ziegler, D., Marshall, G. M., Gurova, K., Burkhart, C., Purmal, A., Gudkov, A. V., Norris, M. D., Haber, M., Murray, J., Gamble, L., Carnegie-Clark, A., Webber, H., Ruhle, M., Carter, D., Oberthur, A., Fischer, M., Ziegler, D., Marshall, G. M., Gurova, K., Burkhart, C., Purmal, A., Gudkov, A. V., and Norris, M. D.
Published: 2014

20. 422 CBL0137, a novel NFkB suppressor and p53 activator, is highly effective in pre-clinical models of neuroblastoma

Author: Haber, M., primary, Murray, J., additional, Gamble, L., additional, Carnegie-Clark, A., additional, Webber, H., additional, Ruhle, M., additional, Carter, D., additional, Oberthur, A., additional, Fischer, M., additional, Ziegler, D., additional, Marshall, G.M., additional, Gurova, K., additional, Burkhart, C., additional, Purmal, A., additional, Gudkov, A.V., additional, and Norris, M.D., additional
Published: 2014
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21. Integrated high-throughput analysis identifies Sp1 as a crucial determinant of p53-mediated apoptosis

Author: Li, H, primary, Zhang, Y, additional, Ströse, A, additional, Tedesco, D, additional, Gurova, K, additional, and Selivanova, G, additional
Published: 2014
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22. HIGH GRADE GLIOMAS AND DIPG

Author: Classen, C. F., primary, William, D., additional, Linnebacher, M., additional, Farhod, A., additional, Kedr, W., additional, Elsabe, B., additional, Fadel, S., additional, Van Gool, S., additional, De Vleeschouwer, S., additional, Koks, C., additional, Garg, A., additional, Ehrhardt, M., additional, Riva, M., additional, Agostinis, P., additional, Graf, N., additional, Yao, T.-W., additional, Yoshida, Y., additional, Zhang, J., additional, Ozawa, T., additional, James, D., additional, Nicolaides, T., additional, Kebudi, R., additional, Cakir, F. B., additional, Gorgun, O., additional, Agaoglu, F. Y., additional, Darendeliler, E., additional, Al-Kofide, A., additional, Al-Shail, E., additional, Khafaga, Y., additional, Al-Hindi, H., additional, Dababo, M., additional, Haq, A. U., additional, Anas, M., additional, Barria, M. G., additional, Siddiqui, K., additional, Hassounah, M., additional, Ayas, M., additional, van Zanten, S. V., additional, Jansen, M., additional, van Vuurden, D., additional, Huisman, M., additional, Vugts, D., additional, Hoekstra, O., additional, van Dongen, G., additional, Kaspers, G., additional, Cockle, J., additional, Ilett, E., additional, Scott, K., additional, Bruning-Richardson, A., additional, Picton, S., additional, Short, S., additional, Melcher, A., additional, Benesch, M., additional, Warmuth-Metz, M., additional, von Bueren, A. O., additional, Hoffmann, M., additional, Pietsch, T., additional, Kortmann, R.-D., additional, Eyrich, M., additional, Rutkowski, S., additional, Fruhwald, M. C., additional, Faber, J., additional, Kramm, C., additional, Porkholm, M., additional, Valanne, L., additional, Lonnqvist, T., additional, Holm, S., additional, Lannering, B., additional, Riikonen, P., additional, Wojcik, D., additional, Sehested, A., additional, Clausen, N., additional, Harila-Saari, A., additional, Schomerus, E., additional, Thorarinsdottir, H. K., additional, Lahteenmaki, P., additional, Arola, M., additional, Thomassen, H., additional, Saarinen-Pihkala, U. M., additional, Kivivuori, S.-M., additional, Buczkowicz, P., additional, Hoeman, C., additional, Rakopoulos, P., additional, Pajovic, S., additional, Morrison, A., additional, Bouffet, E., additional, Bartels, U., additional, Becher, O., additional, Hawkins, C., additional, Gould, T. W. A., additional, Rahman, C. V., additional, Smith, S. J., additional, Barrett, D. A., additional, Shakesheff, K. M., additional, Grundy, R. G., additional, Rahman, R., additional, Barua, N., additional, Cronin, D., additional, Gill, S., additional, Lowisl, S., additional, Hochart, A., additional, Maurage, C.-A., additional, Rocourt, N., additional, Vinchon, M., additional, Kerdraon, O., additional, Escande, F., additional, Grill, J., additional, Pick, V. K., additional, Leblond, P., additional, Burzynski, G., additional, Janicki, T., additional, Burzynski, S., additional, Marszalek, A., additional, Ramani, N., additional, Zaky, W., additional, Kannan, G., additional, Morani, A., additional, Sandberg, D., additional, Ketonen, L., additional, Maher, O., additional, Corrales-Medina, F., additional, Meador, H., additional, Khatua, S., additional, Brassesco, M., additional, Delsin, L., additional, Roberto, G., additional, Silva, C., additional, Ana, L., additional, Rego, E., additional, Scrideli, C., additional, Umezawa, K., additional, Tone, L., additional, Kim, S. J., additional, Kim, C.-Y., additional, Kim, I.-A., additional, Han, J. H., additional, Choi, B.-S., additional, Ahn, H. S., additional, Choi, H. S., additional, Haque, F., additional, Layfield, R., additional, Grundy, R., additional, Gandola, L., additional, Pecori, E., additional, Biassoni, V., additional, Schiavello, E., additional, Chiruzzi, C., additional, Spreafico, F., additional, Modena, P., additional, Bach, F., additional, Pignoli, E., additional, Massimino, M., additional, Drogosiewicz, M., additional, Dembowska-Baginska, B., additional, Jurkiewicz, E., additional, Filipek, I., additional, Perek-Polnik, M., additional, Swieszkowska, E., additional, Perek, D., additional, Bender, S., additional, Jones, D. T., additional, Warnatz, H.-J., additional, Hutter, B., additional, Zichner, T., additional, Gronych, J., additional, Korshunov, A., additional, Eils, R., additional, Korbel, J. O., additional, Yaspo, M.-L., additional, Lichter, P., additional, Pfister, S. M., additional, Yadavilli, S., additional, Becher, O. J., additional, Kambhampati, M., additional, Packer, R. J., additional, Nazarian, J., additional, Lechon, F. C., additional, Fowkes, L., additional, Khabra, K., additional, Martin-Retortillo, L. M., additional, Marshall, L. V., additional, Vaidya, S., additional, Koh, D.-M., additional, Leach, M. O., additional, Pearson, A. D., additional, Zacharoulis, S., additional, Schrey, D., additional, Barone, G., additional, Panditharatna, E., additional, Stampar, M., additional, Siu, A., additional, Gordish-Dressman, H., additional, Devaney, J., additional, Hwang, E. I., additional, Chung, A. H., additional, Mittapalli, R. K., additional, Elmquist, W. F., additional, Castel, D., additional, Debily, M.-A., additional, Philippe, C., additional, Truffaux, N., additional, Taylor, K., additional, Calmon, R., additional, Boddaert, N., additional, Le Dret, L., additional, Saulnier, P., additional, Lacroix, L., additional, Mackay, A., additional, Jones, C., additional, Puget, S., additional, Sainte-Rose, C., additional, Blauwblomme, T., additional, Varlet, P., additional, Entz-Werle, N., additional, Maugard, C., additional, Bougeard, G., additional, Nguyen, A., additional, Chenard, M. P., additional, Schneider, A., additional, Gaub, M. P., additional, Tsoli, M., additional, Vanniasinghe, A., additional, Luk, P., additional, Dilda, P., additional, Haber, M., additional, Hogg, P., additional, Ziegler, D., additional, Simon, S., additional, Monje, M., additional, Gurova, K., additional, Gudkov, A., additional, Zapotocky, M., additional, Churackova, M., additional, Malinova, B., additional, Zamecnik, J., additional, Kyncl, M., additional, Tichy, M., additional, Puchmajerova, A., additional, Stary, J., additional, Sumerauer, D., additional, Boult, J., additional, Vinci, M., additional, Perryman, L., additional, Box, G., additional, Jury, A., additional, Popov, S., additional, Ingram, W., additional, Eccles, S., additional, Robinson, S., additional, Emir, S., additional, Demir, H. A., additional, Bayram, C., additional, Cetindag, F., additional, Kabacam, G. B., additional, Fettah, A., additional, Li, J., additional, Jamin, Y., additional, Cummings, C., additional, Bamber, J., additional, Sinkus, R., additional, Nandhabalan, M., additional, Bjerke, L., additional, Burford, A., additional, von Bueren, A., additional, Baudis, M., additional, Clarke, P., additional, Collins, I., additional, Workman, P., additional, Olaciregui, N., additional, Mora, J., additional, Carcaboso, A., additional, Bullock, A., additional, Alonso, M., additional, de Torres, C., additional, Cruz, O., additional, Pencreach, E., additional, Moussalieh, F. M., additional, Guenot, D., additional, Namer, I., additional, Pollack, I., additional, Jakacki, R., additional, Butterfield, L., additional, Hamilton, R., additional, Panigrahy, A., additional, Potter, D., additional, Connelly, A., additional, Dibridge, S., additional, Whiteside, T., additional, Okada, H., additional, Ahsan, S., additional, Raabe, E., additional, Haffner, M., additional, Warren, K., additional, Quezado, M., additional, Ballester, L., additional, Eberhart, C., additional, Rodriguez, F., additional, Ramachandran, C., additional, Nair, S., additional, Quirrin, K.-W., additional, Khatib, Z., additional, Escalon, E., additional, Melnick, S., additional, Classen, C. F., additional, Hofmann, M., additional, Schmid, I., additional, Simon, T., additional, Maass, E., additional, Russo, A., additional, Fleischhack, G., additional, Becker, M., additional, Hauch, H., additional, Sander, A., additional, Grasso, C., additional, Berlow, N., additional, Liu, L., additional, Davis, L., additional, Huang, E., additional, Woo, P., additional, Tang, Y., additional, Ponnuswami, A., additional, Chen, S., additional, Huang, Y., additional, Hutt-Cabezas, M., additional, Dret, L., additional, Meltzer, P., additional, Mao, H., additional, Abraham, J., additional, Fouladi, M., additional, Svalina, M. N., additional, Wang, N., additional, Hulleman, E., additional, Li, X.-N., additional, Keller, C., additional, Spellman, P. T., additional, Pal, R., additional, Jansen, M. H. A., additional, Sewing, A. C. P., additional, Lagerweij, T., additional, Vuchts, D. J., additional, van Vuurden, D. G., additional, Caretti, V., additional, Wesseling, P., additional, Kaspers, G. J. L., additional, Cohen, K., additional, Pearl, M., additional, Kogiso, M., additional, Zhang, L., additional, Qi, L., additional, Lindsay, H., additional, Lin, F., additional, Berg, S., additional, Muscal, J., additional, Amayiri, N., additional, Tabori, U., additional, Campbel, B., additional, Bakry, D., additional, Aronson, M., additional, Durno, C., additional, Gallinger, S., additional, Malkin, D., additional, Qaddumi, I., additional, Musharbash, A., additional, Swaidan, M., additional, Al-Hussaini, M., additional, Shandilya, S., additional, McCully, C., additional, Murphy, R., additional, Akshintala, S., additional, Cole, D., additional, Macallister, R. P., additional, Cruz, R., additional, Widemann, B., additional, Salloum, R., additional, Smith, A., additional, Glaunert, M., additional, Ramkissoon, A., additional, Peterson, S., additional, Baker, S., additional, Chow, L., additional, Sandgren, J., additional, Pfeifer, S., additional, Popova, S., additional, Alafuzoff, I., additional, de Stahl, T. D., additional, Pietschmann, S., additional, Kerber, M. J., additional, Zwiener, I., additional, Henke, G., additional, Muller, K., additional, Sieow, N. Y.-F., additional, Hoe, R. H. M., additional, Tan, A. M., additional, Chan, M. Y., additional, Soh, S. Y., additional, Burrell, K., additional, Chornenkyy, Y., additional, Remke, M., additional, Golbourn, B., additional, Barzczyk, M., additional, Taylor, M., additional, Rutka, J., additional, Dirks, P., additional, Zadeh, G., additional, Agnihotri, S., additional, Hashizume, R., additional, Ihara, Y., additional, Andor, N., additional, Chen, X., additional, Lerner, R., additional, Huang, X., additional, Tom, M., additional, Solomon, D., additional, Mueller, S., additional, Petritsch, C., additional, Zhang, Z., additional, Gupta, N., additional, Waldman, T., additional, Dujua, A., additional, Co, J., additional, Hernandez, F., additional, Doromal, D., additional, Hegde, M., additional, Wakefield, A., additional, Brawley, V., additional, Grada, Z., additional, Byrd, T., additional, Chow, K., additional, Krebs, S., additional, Heslop, H., additional, Gottschalk, S., additional, Yvon, E., additional, Ahmed, N., additional, Cornilleau, G., additional, Paulsson, J., additional, Andreiuolo, F., additional, Guerrini-Rousseau, L., additional, Geoerger, B., additional, Vassal, G., additional, Ostman, A., additional, Parsons, D. W., additional, Trevino, L. R., additional, Gao, F., additional, Shen, X., additional, Hampton, O., additional, Kosigo, M., additional, Baxter, P. A., additional, Su, J. M., additional, Chintagumpala, M., additional, Dauser, R., additional, Adesina, A., additional, Plon, S. E., additional, Wheeler, D. A., additional, Lau, C. C., additional, Gielen, G., additional, Muehlen, A. z., additional, Kwiecien, R., additional, Wolff, J., additional, Lulla, R. R., additional, Laskowski, J., additional, Goldman, S., additional, Gopalakrishnan, V., additional, Fangusaro, J., additional, Kieran, M., additional, Fontebasso, A., additional, Papillon-Cavanagh, S., additional, Schwartzentruber, J., additional, Nikbakht, H., additional, Gerges, N., additional, Fiset, P.-O., additional, Bechet, D., additional, Faury, D., additional, De Jay, N., additional, Ramkissoon, L., additional, Corcoran, A., additional, Jones, D., additional, Sturm, D., additional, Johann, P., additional, Tomita, T., additional, Nagib, M., additional, Bendel, A., additional, Goumnerova, L., additional, Bowers, D. C., additional, Leonard, J. R., additional, Rubin, J. B., additional, Alden, T., additional, DiPatri, A., additional, Browd, S., additional, Leary, S., additional, Jallo, G., additional, Prados, M. D., additional, Banerjee, A., additional, Carret, A.-S., additional, Ellezam, B., additional, Crevier, L., additional, Klekner, A., additional, Bognar, L., additional, Hauser, P., additional, Garami, M., additional, Myseros, J., additional, Dong, Z., additional, Siegel, P. M., additional, Gump, W., additional, Ayyanar, K., additional, Ragheb, J., additional, Krieger, M., additional, Kiehna, E., additional, Robison, N., additional, Harter, D., additional, Gardner, S., additional, Handler, M., additional, Foreman, N., additional, Brahma, B., additional, MacDonald, T., additional, Malkin, H., additional, Chi, S., additional, Manley, P., additional, Bandopadhayay, P., additional, Greenspan, L., additional, Ligon, A., additional, Albrecht, S., additional, Ligon, K. L., additional, Majewski, J., additional, Jabado, N., additional, Cordero, F., additional, Halvorson, K., additional, Taylor, I., additional, Hutt, M., additional, Weingart, M., additional, Price, A., additional, Kantar, M., additional, Onen, S., additional, Kamer, S., additional, Turhan, T., additional, Kitis, O., additional, Ertan, Y., additional, Cetingul, N., additional, Anacak, Y., additional, Akalin, T., additional, Ersahin, Y., additional, Mason, G., additional, Ho, C., additional, Crozier, F., additional, Vezina, G., additional, Packer, R., additional, Hwang, E., additional, Gilheeney, S., additional, Millard, N., additional, DeBraganca, K., additional, Khakoo, Y., additional, Kramer, K., additional, Wolden, S., additional, Donzelli, M., additional, Fischer, C., additional, Petriccione, M., additional, Dunkel, I., additional, Afzal, S., additional, Fleming, A., additional, Larouche, V., additional, Zelcer, S., additional, Johnston, D. L., additional, Kostova, M., additional, Mpofu, C., additional, Decarie, J.-C., additional, Strother, D., additional, Lafay-Cousin, L., additional, Eisenstat, D., additional, Fryer, C., additional, Hukin, J., additional, Hsu, M., additional, Lasky, J., additional, Moore, T., additional, Liau, L., additional, Davidson, T., additional, Prins, R., additional, Hassal, T., additional, Baugh, J., additional, Kirkendall, J., additional, Doughman, R., additional, Leach, J., additional, Jones, B., additional, Miles, L., additional, Hargrave, D., additional, Jacques, T., additional, Savage, S., additional, Saunders, D., additional, Wallace, R., additional, Flutter, B., additional, Morgenestern, D., additional, Blanco, E., additional, Howe, K., additional, Lowdell, M., additional, Samuel, E., additional, Michalski, A., additional, Anderson, J., additional, Arakawa, Y., additional, Umeda, K., additional, Watanabe, K.-i., additional, Mizowaki, T., additional, Hiraoka, M., additional, Hiramatsu, H., additional, Adachi, S., additional, Kunieda, T., additional, Takagi, Y., additional, Miyamoto, S., additional, Venneti, S., additional, Santi, M., additional, Felicella, M. M., additional, Sullivan, L. M., additional, Dolgalev, I., additional, Martinez, D., additional, Perry, A., additional, Lewis, P. W., additional, Allis, D. C., additional, Thompson, C. B., additional, and Judkins, A. R., additional
Published: 2014
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23. EXPERIMENTAL THERAPEUTICS AND PHARMACOLOGY

Author: Aaberg-Jessen, C., primary, Fogh, L., additional, Halle, B., additional, Jensen, V., additional, Brunner, N., additional, Kristensen, B. W., additional, Abe, T., additional, Momii, Y., additional, Watanabe, J., additional, Morisaki, I., additional, Natsume, A., additional, Wakabayashi, T., additional, Fujiki, M., additional, Aldaz, B., additional, Fabius, A. W. M., additional, Silber, J., additional, Harinath, G., additional, Chan, T. A., additional, Huse, J. T., additional, Anai, S., additional, Hide, T., additional, Nakamura, H., additional, Makino, K., additional, Yano, S., additional, Kuratsu, J.-i., additional, Balyasnikova, I. V., additional, Prasol, M. S., additional, Kanoija, D. K., additional, Aboody, K. S., additional, Lesniak, M. S., additional, Barone, T., additional, Burkhart, C., additional, Purmal, A., additional, Gudkov, A., additional, Gurova, K., additional, Plunkett, R., additional, Barton, K., additional, Misuraca, K., additional, Cordero, F., additional, Dobrikova, E., additional, Min, H., additional, Gromeier, M., additional, Kirsch, D., additional, Becher, O., additional, Pont, L. B., additional, Kloezeman, J., additional, van den Bent, M., additional, Kanaar, R., additional, Kremer, A., additional, Swagemakers, S., additional, French, P., additional, Dirven, C., additional, Lamfers, M., additional, Leenstra, S., additional, Balvers, R., additional, Kleijn, A., additional, Lawler, S., additional, Gong, X., additional, Andres, A., additional, Hanson, J., additional, Delashaw, J., additional, Bota, D., additional, Chen, C.-C., additional, Yao, N.-W., additional, Chuang, W.-J., additional, Chang, C., additional, Chen, P.-Y., additional, Huang, C.-Y., additional, Wei, K.-C., additional, Cheng, Y., additional, Dai, Q., additional, Morshed, R., additional, Han, Y., additional, Auffinger, B., additional, Wainwright, D., additional, Zhang, L., additional, Tobias, A., additional, Rincon, E., additional, Thaci, B., additional, Ahmed, A., additional, He, C., additional, Lesniak, M., additional, Choi, Y. A., additional, Pandya, H., additional, Gibo, D. M., additional, Fokt, I., additional, Priebe, W., additional, Debinski, W., additional, Chornenkyy, Y., additional, Agnihotri, S., additional, Buczkowicz, P., additional, Rakopoulos, P., additional, Morrison, A., additional, Barszczyk, M., additional, Hawkins, C., additional, Chung, S., additional, Decollogne, S., additional, Luk, P., additional, Shen, H., additional, Ha, W., additional, Day, B., additional, Stringer, B., additional, Hogg, P., additional, Dilda, P., additional, McDonald, K., additional, Moore, S., additional, Hayden-Gephart, M., additional, Bergen, J., additional, Su, Y., additional, Rayburn, H., additional, Edwards, M., additional, Scott, M., additional, Cochran, J., additional, Das, A., additional, Varma, A. K., additional, Wallace, G. C., additional, Dixon-Mah, Y. N., additional, Vandergrift, W. A., additional, Giglio, P., additional, Ray, S. K., additional, Patel, S. J., additional, Banik, N. L., additional, Dasgupta, T., additional, Olow, A., additional, Yang, X., additional, Mueller, S., additional, Prados, M., additional, James, C. D., additional, Haas-Kogan, D., additional, Dave, N. D., additional, Desai, P. B., additional, Gudelsky, G. A., additional, Chow, L. M. L., additional, LaSance, K., additional, Qi, X., additional, Driscoll, J., additional, Ebsworth, K., additional, Walters, M. J., additional, Ertl, L. S., additional, Wang, Y., additional, Berahovic, R. D., additional, McMahon, J., additional, Powers, J. P., additional, Jaen, J. C., additional, Schall, T. J., additional, Eroglu, Z., additional, Portnow, J., additional, Sacramento, A., additional, Garcia, E., additional, Raubitschek, A., additional, Synold, T., additional, Esaki, S., additional, Rabkin, S., additional, Martuza, R., additional, Wakimoto, H., additional, Ferluga, S., additional, Tome, C. L., additional, Forde, H. E., additional, Netland, I. A., additional, Sleire, L., additional, Skeie, B., additional, Enger, P. O., additional, Goplen, D., additional, Giladi, M., additional, Tichon, A., additional, Schneiderman, R., additional, Porat, Y., additional, Munster, M., additional, Dishon, M., additional, Weinberg, U., additional, Kirson, E., additional, Wasserman, Y., additional, Palti, Y., additional, Gramatzki, D., additional, Staudinger, M., additional, Frei, K., additional, Peipp, M., additional, Weller, M., additional, Grasso, C., additional, Liu, L., additional, Berlow, N., additional, Davis, L., additional, Fouladi, M., additional, Gajjar, A., additional, Huang, E., additional, Hulleman, E., additional, Hutt, M., additional, Keller, C., additional, Li, X.-N., additional, Meltzer, P., additional, Quezado, M., additional, Quist, M., additional, Raabe, E., additional, Spellman, P., additional, Truffaux, N., additional, van Vurden, D., additional, Wang, N., additional, Warren, K., additional, Pal, R., additional, Grill, J., additional, Monje, M., additional, Green, A. L., additional, Ramkissoon, S., additional, McCauley, D., additional, Jones, K., additional, Perry, J. A., additional, Ramkissoon, L., additional, Maire, C., additional, Shacham, S., additional, Ligon, K. L., additional, Kung, A. L., additional, Zielinska-Chomej, K., additional, Grozman, V., additional, Tu, J., additional, Viktorsson, K., additional, Lewensohn, R., additional, Gupta, S., additional, Mladek, A., additional, Bakken, K., additional, Carlson, B., additional, Boakye-Agyeman, F., additional, Kizilbash, S., additional, Schroeder, M., additional, Reid, J., additional, Sarkaria, J., additional, Hadaczek, P., additional, Ozawa, T., additional, Soroceanu, L., additional, Yoshida, Y., additional, Matlaf, L., additional, Singer, E., additional, Fiallos, E., additional, Cobbs, C. S., additional, Hashizume, R., additional, Tom, M., additional, Ihara, Y., additional, Santos, R., additional, Torre, J. D. L., additional, Lepe, E., additional, Waldman, T., additional, James, D., additional, Huang, X., additional, Yu-Jen, L., additional, Gupta, N., additional, Solomon, D., additional, Zhang, Z., additional, Hayashi, T., additional, Adachi, K., additional, Nagahisa, S., additional, Hasegawa, M., additional, Hirose, Y., additional, Gephart, M. H., additional, Su, Y. S., additional, Hingtgen, S., additional, Kasmieh, R., additional, Nesterenko, I., additional, Figueiredo, J.-L., additional, Dash, R., additional, Sarkar, D., additional, Fisher, P., additional, Shah, K., additional, Horne, E., additional, Diaz, P., additional, Stella, N., additional, Huang, C., additional, Yang, H., additional, Wei, K., additional, Huang, T., additional, Hlavaty, J., additional, Ostertag, D., additional, Espinoza, F. L., additional, Martin, B., additional, Petznek, H., additional, Rodriguez-Aguirre, M., additional, Ibanez, C., additional, Kasahara, N., additional, Gunzburg, W., additional, Gruber, H., additional, Pertschuk, D., additional, Jolly, D., additional, Robbins, J., additional, Hurwitz, B., additional, Yoo, J. Y., additional, Bolyard, C., additional, Yu, J.-G., additional, Wojton, J., additional, Zhang, J., additional, Bailey, Z., additional, Eaves, D., additional, Cripe, T., additional, Old, M., additional, Kaur, B., additional, Serwer, L., additional, Le Moan, N., additional, Ng, S., additional, Butowski, N., additional, Krtolica, A., additional, Cary, S. P. L., additional, Johns, T., additional, Greenall, S., additional, Donoghue, J., additional, Adams, T., additional, Karpel-Massler, G., additional, Westhoff, M.-A., additional, Kast, R. E., additional, Dwucet, A., additional, Wirtz, C. R., additional, Debatin, K.-M., additional, Halatsch, M.-E., additional, Merkur, N., additional, Kievit, F., additional, Stephen, Z., additional, Wang, K., additional, Kolstoe, D., additional, Ellenbogen, R., additional, Zhang, M., additional, Kitange, G., additional, Haefner, E., additional, Knubel, K., additional, Pernu, B. M., additional, Sufit, A., additional, Pierce, A. M., additional, Nelson, S. K., additional, Keating, A. K., additional, Jensen, S. S., additional, Lachowicz, J., additional, Demeule, M., additional, Regina, A., additional, Tripathy, S., additional, Curry, J.-C., additional, Nguyen, T., additional, Castaigne, J.-P., additional, Davis, T., additional, Davis, A., additional, Tanaka, K., additional, Keating, T., additional, Getz, J., additional, Kapp, G. T., additional, Romero, J. M., additional, Lee, S., additional, Ramisetti, S., additional, Slagle-Webb, B., additional, Sharma, A., additional, Connor, J., additional, Lee, W.-S., additional, Kluk, M., additional, Aster, J. C., additional, Ligon, K., additional, Sun, S., additional, Lee, D., additional, Ho, A. S. W., additional, Pu, J. K. S., additional, Zhang, Z.-q., additional, Lee, N. P., additional, Day, P. J. R., additional, Leung, G. K. K., additional, Liu, Z., additional, Liu, X., additional, Madhankumar, A. B., additional, Miller, P., additional, Webb, B., additional, Connor, J. R., additional, Yang, Q. X., additional, Lobo, M., additional, Green, S., additional, Schabel, M., additional, Gillespie, Y., additional, Woltjer, R., additional, Pike, M., additional, Lu, Y.-J., additional, Luchman, H. A., additional, Stechishin, O., additional, Nguyen, S., additional, Cairncross, J. G., additional, Weiss, S., additional, Lun, X., additional, Wells, J. C., additional, Hao, X., additional, Grinshtein, N., additional, Kaplan, D., additional, Luchman, A., additional, Senger, D., additional, Robbins, S., additional, Madhankumar, A., additional, Rizk, E., additional, Payne, R., additional, Park, A., additional, Pang, M., additional, Harbaugh, K., additional, Wilisch-Neumann, A., additional, Pachow, D., additional, Kirches, E., additional, Mawrin, C., additional, McDonell, S., additional, Liang, J., additional, Piao, Y., additional, Nguyen, N., additional, Yung, A., additional, Verhaak, R., additional, Sulman, E., additional, Stephan, C., additional, Lang, F., additional, de Groot, J., additional, Mizobuchi, Y., additional, Okazaki, T., additional, Kageji, T., additional, Kuwayama, K., additional, Kitazato, K. T., additional, Mure, H., additional, Hara, K., additional, Morigaki, R., additional, Matsuzaki, K., additional, Nakajima, K., additional, Nagahiro, S., additional, Kumala, S., additional, Heravi, M., additional, Devic, S., additional, Muanza, T., additional, Knubel, K. H., additional, Neuwelt, A., additional, Wu, Y. J., additional, Donson, A., additional, Vibhakar, R., additional, Venkatamaran, S., additional, Amani, V., additional, Neuwelt, E., additional, Rapkin, L., additional, Foreman, N., additional, Ibrahim, F., additional, New, P., additional, Cui, K., additional, Zhao, H., additional, Chow, D., additional, Stephen, W., additional, Nozue-Okada, K., additional, Nagane, M., additional, McDonald, K. L., additional, Ogawa, D., additional, Chiocca, E., additional, Godlewski, J., additional, Patel, A., additional, Pasupuleti, N., additional, Gorin, F., additional, Valenzuela, A., additional, Leon, L., additional, Carraway, K., additional, Ramachandran, C., additional, Nair, S., additional, Quirrin, K.-W., additional, Khatib, Z., additional, Escalon, E., additional, Melnick, S., additional, Phillips, A., additional, Boghaert, E., additional, Vaidya, K., additional, Ansell, P., additional, Shalinsky, D., additional, Zhang, Y., additional, Voorbach, M., additional, Mudd, S., additional, Holen, K., additional, Humerickhouse, R., additional, Reilly, E., additional, Parab, S., additional, Diago, O., additional, Ryken, T., additional, Agarwal, S., additional, Al-Keilani, M., additional, Alqudah, M., additional, Sibenaller, Z., additional, Assemolt, M., additional, Sai, K., additional, Li, W.-y., additional, Li, W.-p., additional, Chen, Z.-p., additional, Saito, R., additional, Sonoda, Y., additional, Kanamori, M., additional, Yamashita, Y., additional, Kumabe, T., additional, Tominaga, T., additional, Sarkar, G., additional, Curran, G., additional, Jenkins, R., additional, Scharnweber, R., additional, Kato, Y., additional, Lin, J., additional, Everson, R., additional, Soto, H., additional, Kruse, C., additional, Liau, L., additional, Prins, R., additional, Semenkow, S., additional, Chu, Q., additional, Eberhart, C., additional, Sengupta, R., additional, Marassa, J., additional, Piwnica-Worms, D., additional, Rubin, J., additional, Shai, R., additional, Pismenyuk, T., additional, Moshe, I., additional, Fisher, T., additional, Freedman, S., additional, Simon, A., additional, Amariglio, N., additional, Rechavi, G., additional, Toren, A., additional, Yalon, M., additional, Shimazu, Y., additional, Kurozumi, K., additional, Ichikawa, T., additional, Fujii, K., additional, Onishi, M., additional, Ishida, J., additional, Oka, T., additional, Watanabe, M., additional, Nasu, Y., additional, Kumon, H., additional, Date, I., additional, Sirianni, R. W., additional, McCall, R. L., additional, Spoor, J., additional, van der Kaaij, M., additional, Geurtjens, M., additional, Veiseh, O., additional, Fang, C., additional, Leung, M., additional, Strohbehn, G., additional, Atsina, K.-K., additional, Patel, T., additional, Piepmeier, J., additional, Zhou, J., additional, Saltzman, W. M., additional, Takahashi, M., additional, Valdes, G., additional, Inagaki, A., additional, Kamijima, S., additional, Hiraoka, K., additional, Micewicz, E., additional, McBride, W. H., additional, Iwamoto, K. S., additional, Gruber, H. E., additional, Robbins, J. M., additional, Jolly, D. J., additional, McCully, C., additional, Bacher, J., additional, Thomas, T., additional, Murphy, R., additional, Steffen-Smith, E., additional, McAllister, R., additional, Pastakia, D., additional, Widemann, B., additional, Chen, P., additional, Hua, M., additional, Liu, H., additional, Woolf, E. C., additional, Abdelwahab, M. G., additional, Fenton, K. E., additional, Liu, Q., additional, Turner, G., additional, Preul, M. C., additional, Scheck, A. C., additional, Shen, W., additional, Brown, D., additional, Pedersen, H., additional, Hariono, S., additional, Yao, T.-W., additional, Sidhu, A., additional, Weiss, W. A., additional, Nicolaides, T. P., additional, and Olusanya, T., additional
Published: 2013
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24. Inflammation and p53: A Tale of Two Stresses

Author: Gudkov, A. V., primary, Gurova, K. V., additional, and Komarova, E. A., additional
Published: 2011
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25. Study on the Thermochemical and Kinetic Characteristics of Alkali Treated Rice Husk

Author: Markovska, I. G., primary, Bogdanov, B., additional, Nedelchev, N. M., additional, Gurova, K. M., additional, Zagorcheva, M. H., additional, and Lyubchev, L. A., additional
Published: 2010
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26. High expression of shMDG1 gene is associated with low metastatic potential of tumor cells

Author: Isachenko, N, primary, Dyakova, N, additional, Aushev, V, additional, Chepurnych, T, additional, Gurova, K, additional, and Tatosyan, A, additional
Published: 2005
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27. Targeted disruption of the mouse ing1 locus results in reduced body size, hypersensitivity to radiation and elevated incidence of lymphomas

Author: Kichina, J V, primary, Zeremski, M, additional, Aris, L, additional, Gurova, K V, additional, Walker, E, additional, Franks, R, additional, Nikitin, A Y, additional, Kiyokawa, H, additional, and Gudkov, A V, additional
Published: 2005
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28. Structure and regulation of the mouse ing1 gene. Three alternative transcripts encode two phd finger proteins that have opposite effects on p53 function.

Author: Zeremski, M, Hill, J E, Kwek, S S, Grigorian, I A, Gurova, K V, Garkavtsev, I V, Diatchenko, L, Koonin, E V, and Gudkov, A V
Abstract: The human ING1 gene encodes nuclear protein p33(ING1), previously shown to cooperate with p53 in cell growth control (Garkavtsev, I., Grigorian, I. A., Ossovskaya, V. S., Chernov, M. V., Chumakov, P. M., and Gudkov, A. V. (1998) Nature 391, 295-298). p33(ING1) belongs to a small family of proteins from human, mouse, and yeast of approximately the same size that show significant similarity to one another within the C-terminal PHD finger domain and also contain an additional N-terminal region with subtle but reliably detectable sequence conservation. Mouse ing1 is transcribed from three differently regulated promoters localized within a 4-kilobase pair region of genomic DNA. The resulting transcripts share a long common region encoded by a common exon and differ in their 5'-exon sequences. Two transcripts are translated into the same protein of 185 amino acids, the mouse equivalent of the human p33(ING1), while the third transcript encodes a longer protein that has 94 additional N-terminal amino acids. Overexpression of the longer protein interferes with the accumulation of p53 protein and activation of p53-responsive promoters after DNA damage. Between the two products of ing1, only the longer one forms a complex with p53 detectable by immunoprecipitation. These results indicate that a single gene, ing1, encodes both p53-suppressing and p53-activating proteins that are regulated by alternative promoters.
Published: 1999

29. Cooperation of two mutant p53 alleles contributes to Fas resistance of prostate carcinoma cells

Author: Gurova, K. V., Rokhlin, O. W., Andrei Budanov, Burdelya, L. G., Chumakov, P. M., Cohen, M. B., and Gudkov, A. V.

30. Dual targeting of the epigenome via FACT complex and histone deacetylase is a potent treatment strategy for DIPG

Author: Swapna Joshi, Murray D. Norris, Sandy Simon, Orazio Vittorio, Sylvie Shen, Andrei V. Gudkov, Ornella Tolhurst, Anahid Ehteda, Caitlin Ung, Jourdin R. C. Rouaen, Ruby Pandher, Aaminah Khan, Michelle Haber, Elisha Hayden, Laura Franshaw, Rebecca Lehmann, Chelsea Mayoh, Yujie Tang, Katerina Gurova, David S. Ziegler, Maria Tsoli, Federico M. Giorgi, Anjana Gopalakrishnan, Jie Liu, Chi Nam Ignatius Pang, Anne Kankean, Peter Trebilcock, Ehteda A., Simon S., Franshaw L., Giorgi F.M., Liu J., Joshi S., Rouaen J.R.C., Pang C.N.I., Pandher R., Mayoh C., Tang Y., Khan A., Ung C., Tolhurst O., Kankean A., Hayden E., Lehmann R., Shen S., Gopalakrishnan A., Trebilcock P., Gurova K., Gudkov A.V., Norris M.D., Haber M., Vittorio O., Tsoli M., and Ziegler D.S.
Subjects: 0301 basic medicine, xenograft model, Cell Cycle Proteins, Retinoblastoma Protein, Epigenesis, Genetic, Histones, Epigenome, Mice, chemistry.chemical_compound, 0302 clinical medicine, facilitates chromatin transcription complex, HDAC, Panobinostat, Brain Stem Neoplasms, Biology (General), Child, EZH2, Histone deacetylase inhibitor, High Mobility Group Proteins, Acetylation, Drug Synergism, Chromatin, pediatric cancer, DNA-Binding Proteins, DIPG, Transcriptional Elongation Factors, Neuroglia, Signal Transduction, medicine.drug_class, QH301-705.5, Primary Cell Culture, Carbazoles, Antineoplastic Agents, Methylation, General Biochemistry, Genetics and Molecular Biology, Chromatin remodeling, 03 medical and health sciences, H3K27M, Cell Line, Tumor, medicine, Animals, Humans, anticancer therapy, Histone H3 acetylation, Diffuse Intrinsic Pontine Glioma, brainstem glioma, Survival Analysis, Xenograft Model Antitumor Assays, Pediatric cancer, 030104 developmental biology, chemistry, E2F1, Cancer research, Histone deacetylase, Tumor Suppressor Protein p53, E2F1 Transcription Factor, 030217 neurology & neurosurgery, Transcription Factors
Abstract: Summary: Diffuse intrinsic pontine glioma (DIPG) is an aggressive and incurable childhood brain tumor for which new treatments are needed. CBL0137 is an anti-cancer compound developed from quinacrine that targets facilitates chromatin transcription (FACT), a chromatin remodeling complex involved in transcription, replication, and DNA repair. We show that CBL0137 displays profound cytotoxic activity against a panel of patient-derived DIPG cultures by restoring tumor suppressor TP53 and Rb activity. Moreover, in an orthotopic model of DIPG, treatment with CBL0137 significantly extends animal survival. The FACT subunit SPT16 is found to directly interact with H3.3K27M, and treatment with CBL0137 restores both histone H3 acetylation and trimethylation. Combined treatment of CBL0137 with the histone deacetylase inhibitor panobinostat leads to inhibition of the Rb/E2F1 pathway and induction of apoptosis. The combination of CBL0137 and panobinostat significantly prolongs the survival of mice bearing DIPG orthografts, suggesting a potential treatment strategy for DIPG.
Published: 2021

31. Image-Based Quantitative Single-Cell Method Showed Increase of Global Chromatin Accessibility in Tumor Compared to Normal Cells.

Author: Commane M, Jadhav V, Leonova K, Buckley B, Withers H, and Gurova K
Abstract: The phenotypic plasticity of cancer cells has recently emerged as an important factor of treatment failure. The mechanisms of phenotypic plasticity are not fully understood. One of the hypotheses is that the degree of chromatin accessibility defines the easiness of cell transitions between different phenotypes. To test this, a method to compare overall chromatin accessibility between cells in a population or between cell populations is needed. We propose to measure chromatin accessibility by fluorescence signal from nuclei of cells stained with DNA binding fluorescent molecules. This method is based on the observations that small molecules bind nucleosome-free DNA more easily than nucleosomal DNA. Thus, nuclear fluorescence is proportional to the amount of nucleosome-free DNA, serving as a measure of chromatin accessibility. We optimized the method using several DNA intercalators and minor groove binders and known chromatin-modulating agents and demonstrated that chromatin accessibility is increased upon oncogene-induced transformation and further in tumor cells., Competing Interests: Competing interests: Authors declare that they have no competing interests. Competing interests: authors declare no competing financial interests in relation to the work described.
Published: 2024
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32. Anticancer Plant Secondary Metabolites Induce Linker Histone Depletion from Chromatin.

Author: Vlasova O, Antonova I, Zenkov R, Naberezhnov D, Belitsky G, Borunova A, Zabotina T, García-Gomis D, Safina A, Gurova K, Gudkov A, Kirsanov K, Jordan A, and Yakubovskaya M
Subjects: Humans, HeLa Cells, Nucleosomes metabolism, Nucleosomes drug effects, Secondary Metabolism, Antineoplastic Agents, Phytogenic pharmacology, Antineoplastic Agents pharmacology, Histones metabolism, Chromatin metabolism
Abstract: Background: Many plant secondary metabolites (PSMs) were shown to intercalate into DNA helix or interact with DNA grooves. This may influence histone-DNA interactions changeing chromatin structure and genome functioning., Methods: Nucleosome stability and linker histone H1.2, H1.4 and H1.5 localizations were studied in HeLa cells after the treatment with 15 PSMs, which are DNA-binders and possess anticancer activity according to published data. Chromatin remodeler CBL0137 was used as a control. Effects of PSMs were studied using fluorescent microscopy, flowcytometry, quantitative reverse transcriptase-polymerase chain reaction (RT-qPCR), western-blotting., Results: We showed that 1-hour treatment with CBL0137 strongly inhibited DNA synthesis and caused intensive linker histone depletion consistent with nucleosome destabilization. None of PSMs caused nucleosome destabilization, while most of them demonstrated significant influence on linker histone localizations. In particular, cell treatment with 11 PSMs at non-toxic concentrations induced significant translocation of the histone H1.5 to nucleoli and most of PSMs caused depletion of the histones H1.2 and H1.4 from chromatin fraction. Curcumin, resveratrol, berberine, naringenin, and quercetin caused significant redistribution of all three variants of the studied linker histones showing some overlap of PSM effects on linker histone DNA-binding. We demonstrated that PSMs, which induced the most significant redistribution of the histone H1.5 (berberine, curcumin and naringenin), influence the proportion of cells synthesizing DNA, expressing or non-expressing cyclin B and influence cell cycle distribution. Berberine induction of H1.5 translocations to nucleoli was shown to occur independently on the phases of cell cycle (metaphase was not analyzed)., Conclusions: For the first time we revealed PSM influence on linker histone location in cell nuclei that opens a new direction of PSM research as anticancer agents., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Published by IMR Press.)
Published: 2024
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33. Chromatin as an old and new anticancer target.

Author: Neefjes J, Gurova K, Sarthy J, Szabó G, and Henikoff S
Subjects: Humans, Molecular Targeted Therapy methods, Anthracyclines therapeutic use, Anthracyclines pharmacology, Animals, Chromatin metabolism, Chromatin drug effects, Neoplasms drug therapy, Neoplasms genetics, Neoplasms pathology, DNA Damage drug effects, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use
Abstract: Recent genome-wide analyses identified chromatin modifiers as one of the most frequently mutated classes of genes across all cancers. However, chemotherapies developed for cancers involving DNA damage remain the standard of care for chromatin-deranged malignancies. In this review we address this conundrum by establishing the concept of 'chromatin damage': the non-genetic damage to protein-DNA interactions induced by certain small molecules. We highlight anthracyclines, a class of chemotherapeutic agents ubiquitously applied in oncology, as an example of overlooked chromatin-targeting agents. We discuss our current understanding of this phenomenon and explore emerging chromatin-damaging agents as a basis for further studies to maximize their impact in modern cancer treatment., Competing Interests: Declaration of interests J.N. has shares in NIHM, a startup aiming to make aclarubicin available to the Western world. K.G. is a coauthor of patents US9108916B2 ‘Carbazole compounds and therapeutic uses of the compounds’, US10434086B2 ‘Combination therapies with curaxins’, and US9169207B2 ‘Curaxins for use in treating carcinogen-induced cancer’., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Published: 2024
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34. Comparison of cell response to chromatin and DNA damage.

Author: Luzhin A, Rajan P, Safina A, Leonova K, Stablewski A, Wang J, Robinson D, Isaeva N, Kantidze O, and Gurova K
Subjects: DNA genetics, DNA metabolism, Histones metabolism, Nucleosomes, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism, Chromatin genetics, DNA Damage
Abstract: DNA-targeting drugs are widely used for anti-cancer treatment. Many of these drugs cause different types of DNA damage, i.e. alterations in the chemical structure of DNA molecule. However, molecules binding to DNA may also interfere with DNA packing into chromatin. Interestingly, some molecules do not cause any changes in DNA chemical structure but interfere with DNA binding to histones and nucleosome wrapping. This results in histone loss from chromatin and destabilization of nucleosomes, a phenomenon that we call chromatin damage. Although the cellular response to DNA damage is well-studied, the consequences of chromatin damage are not. Moreover, many drugs used to study DNA damage also cause chromatin damage, therefore there is no clarity on which effects are caused by DNA or chromatin damage. In this study, we aimed to clarify this issue. We treated normal and tumor cells with bleomycin, nuclease mimicking drug which cut predominantly nucleosome-free DNA and therefore causes DNA damage in the form of DNA breaks, and CBL0137, which causes chromatin damage without direct DNA damage. We describe similarities and differences between the consequences of DNA and chromatin damage. Both agents were more toxic for tumor than normal cells, but while DNA damage causes senescence in both normal and tumor cells, chromatin damage does not. Both agents activated p53, but chromatin damage leads to the accumulation of higher levels of unmodified p53, which transcriptional activity was similar to or lower than that of p53 activated by DNA damage. Most importantly, we found that while transcriptional changes caused by DNA damage are limited by p53-dependent activation of a small number of p53 targets, chromatin damage activated many folds more genes in p53 independent manner., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)
Published: 2023
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35. Targeting Features of Curaxin CBL0137 on Hematological Malignancies In Vitro and In Vivo.

Author: Fetisov TI, Borunova AA, Antipova AS, Antoshina EE, Trukhanova LS, Gorkova TG, Zuevskaya SN, Maslov A, Gurova K, Gudkov A, Lesovaya EA, Belitsky GA, Yakubovskaya MG, and Kirsanov KI
Abstract: The anticancer activity of Curaxin CBL0137, a DNA-binding small molecule with chromatin remodulating effect, has been demonstrated in different cancers. Herein, a comparative evaluation of CBL0137 activity was performed in respect to acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia and multiple myeloma (MM) cultured in vitro. MTT assay showed AML and MM higher sensitivity to CBL0137's cytostatic effect comparatively to other hematological malignancy cells. Flow cytometry cell cycle analysis revealed an increase in subG1 and G2/M populations after CBL0137 cell treatment, but the prevalent type of arrest varied. Apoptosis activation by CBL0137 measured by Annexin-V/PI dual staining was more active in AML and MM cells. RT2 PCR array showed that changes caused by CBL0137 in signaling pathways involved in cancer pathogenesis were more intensive in AML and MM cells. On the murine model of AML WEHI-3, CBL0137 showed significant anticancer effects in vivo, which were evaluated by corresponding changes in spleen and liver. Thus, more pronounced anticancer effects of CBL0137 in vitro were observed in respect to AML and MM. Experiments in vivo also indicated the perspective of CBL0137 use for AML treatment. This in accordance with the frontline treatment approach in AML using epigenetic drugs.
Published: 2023
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36. Can aggressive cancers be identified by the "aggressiveness" of their chromatin?

Author: Gurova K
Subjects: Humans, Nucleosomes genetics, Promoter Regions, Genetic, Transcription, Genetic, Chromatin genetics, Neoplasms genetics
Abstract: Phenotypic plasticity is a crucial feature of aggressive cancer, providing the means for cancer progression. Stochastic changes in tumor cell transcriptional programs increase the chances of survival under any condition. I hypothesize that unstable chromatin permits stochastic transitions between transcriptional programs in aggressive cancers and supports non-genetic heterogeneity of tumor cells as a basis for their adaptability. I present a mechanistic model for unstable chromatin which includes destabilized nucleosomes, mobile chromatin fibers and random enhancer-promoter contacts, resulting in stochastic transcription. I suggest potential markers for "unsettled" chromatin in tumors associated with poor prognosis. Although many of the characteristics of unstable chromatin have been described, they were mostly used to explain changes in the transcription of individual genes. I discuss approaches to evaluate the role of unstable chromatin in non-genetic tumor cell heterogeneity and suggest using the degree of chromatin instability and transcriptional noise in tumor cells to predict cancer aggressiveness., (© 2022 Wiley Periodicals LLC.)
Published: 2022
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37. Targeted Modulation of Interferon Response-Related Genes with IFN-Alpha/Lambda Inhibition.

Author: Sur D, Leonova K, Levi B, Markowitz SI, Cohen-Harazi R, Gitlin I, Gurova K, Gudkov A, Pinhasov A, Koman I, and Nesher E
Subjects: Animals, Antiviral Agents pharmacology, Cytokines metabolism, Inflammation drug therapy, Inflammation genetics, Inflammation metabolism, Mice, Poly I-C pharmacology, Interferon-alpha genetics, Interferon-alpha pharmacology, Interferons genetics
Abstract: Interferon (IFN) signaling resulting from external or internal inflammatory processes initiates the rapid release of cytokines and chemokines to target viral or bacterial invasion, as well as cancer and other diseases. Prolonged exposure to IFNs, or the overexpression of other cytokines, leads to immune exhaustion, enhancing inflammation and leading to the persistence of infection and promotion of disease. Hence, to control and stabilize an excessive immune response, approaches for the management of inflammation are required. The potential use of peptides as anti-inflammatory agents has been previously demonstrated. Our team discovered, and previously published, a 9-amino-acid cyclic peptide named ALOS4 which exhibits anti-cancer properties in vivo and in vitro. We suggested that the anti-cancer effect of ALOS4 arises from interaction with the immune system, possibly through the modulation of inflammatory processes. Here, we show that treatment with ALOS4 decreases basal cytokine levels in mice with chronic inflammation and prolongs the lifespan of mice with acute systemic inflammation induced by irradiation. We also show that pretreatment with ALOS4 reduces the expression of IFN alpha, IFN lambda, and selected interferon-response genes triggered by polyinosinic-polycytidylic acid (Poly I:C), a synthetic analog of viral double-stranded RNA, while upregulating the expression of other genes with antiviral activity. Hence, we conclude that ALOS4 does not prevent IFN signaling, but rather supports the antiviral response by upregulating the expression of interferon-response genes in an interferon-independent manner.
Published: 2022
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38. FACT maintains nucleosomes during transcription and stem cell viability in adult mice.

Author: Goswami I, Sandlesh P, Stablewski A, Toshkov I, Safina AF, Magnitov M, Wang J, and Gurova K
Subjects: Animals, Cell Survival genetics, DNA-Binding Proteins metabolism, Mammals metabolism, Mice, Stem Cells metabolism, Transcription, Genetic, Transcriptional Elongation Factors genetics, High Mobility Group Proteins genetics, High Mobility Group Proteins metabolism, Nucleosomes
Abstract: Preservation of nucleosomes during replication has been extensively studied, while the maintenance of nucleosomes during transcription has gotten less attention. The histone chaperone FACT has a role in transcription elongation, although whether it disassembles or assembles nucleosomes during this process is unclear. To elucidate the function of FACT in mammals, we deleted the Ssrp1 subunit of FACT in adult mice. FACT loss is lethal, possibly due to the loss of the earliest progenitors in bone marrow and intestine, while more differentiated cells are not affected. Using cells isolated from several tissues, we show that FACT loss reduces the viability of stem cells but not of cells differentiated in vitro. FACT depletion increases chromatin accessibility in a transcription-dependent manner in adipose mesenchymal stem cells, indicating that nucleosomes are lost in these cells during transcription in the absence of FACT. We also observe activation of interferon (IFN) signaling and the accumulation of immunocytes in organs sensitive to FACT loss. Our data indicate that FACT maintains chromatin integrity during transcription in mammalian adult stem cells, suggesting that chromatin transcription in stem cells and differentiated cells is different., (© 2022 The Authors.)
Published: 2022
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39. Dual targeting of the epigenome via FACT complex and histone deacetylase is a potent treatment strategy for DIPG.

Author: Ehteda A, Simon S, Franshaw L, Giorgi FM, Liu J, Joshi S, Rouaen JRC, Pang CNI, Pandher R, Mayoh C, Tang Y, Khan A, Ung C, Tolhurst O, Kankean A, Hayden E, Lehmann R, Shen S, Gopalakrishnan A, Trebilcock P, Gurova K, Gudkov AV, Norris MD, Haber M, Vittorio O, Tsoli M, and Ziegler DS
Subjects: Acetylation, Animals, Brain Stem Neoplasms genetics, Brain Stem Neoplasms mortality, Brain Stem Neoplasms pathology, Carbazoles pharmacology, Cell Cycle Proteins genetics, Cell Cycle Proteins metabolism, Cell Line, Tumor, Child, Chromatin chemistry, Chromatin metabolism, DNA-Binding Proteins metabolism, Diffuse Intrinsic Pontine Glioma genetics, Diffuse Intrinsic Pontine Glioma mortality, Diffuse Intrinsic Pontine Glioma pathology, Drug Synergism, E2F1 Transcription Factor genetics, E2F1 Transcription Factor metabolism, Epigenome, High Mobility Group Proteins metabolism, Histones antagonists & inhibitors, Histones metabolism, Humans, Methylation, Mice, Neuroglia metabolism, Neuroglia pathology, Panobinostat pharmacology, Primary Cell Culture, Retinoblastoma Protein genetics, Retinoblastoma Protein metabolism, Signal Transduction, Survival Analysis, Transcription Factors genetics, Transcription Factors metabolism, Transcriptional Elongation Factors metabolism, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, Brain Stem Neoplasms drug therapy, DNA-Binding Proteins genetics, Diffuse Intrinsic Pontine Glioma drug therapy, Epigenesis, Genetic, High Mobility Group Proteins genetics, Histones genetics, Neuroglia drug effects, Transcriptional Elongation Factors genetics
Abstract: Diffuse intrinsic pontine glioma (DIPG) is an aggressive and incurable childhood brain tumor for which new treatments are needed. CBL0137 is an anti-cancer compound developed from quinacrine that targets facilitates chromatin transcription (FACT), a chromatin remodeling complex involved in transcription, replication, and DNA repair. We show that CBL0137 displays profound cytotoxic activity against a panel of patient-derived DIPG cultures by restoring tumor suppressor TP53 and Rb activity. Moreover, in an orthotopic model of DIPG, treatment with CBL0137 significantly extends animal survival. The FACT subunit SPT16 is found to directly interact with H3.3K27M, and treatment with CBL0137 restores both histone H3 acetylation and trimethylation. Combined treatment of CBL0137 with the histone deacetylase inhibitor panobinostat leads to inhibition of the Rb/E2F1 pathway and induction of apoptosis. The combination of CBL0137 and panobinostat significantly prolongs the survival of mice bearing DIPG orthografts, suggesting a potential treatment strategy for DIPG., Competing Interests: Declaration of interests K.G. and A.V.G. are co-inventors on patents describing CBL0137. The remaining authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)
Published: 2021
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40. Histone chaperone FACT is essential to overcome replication stress in mammalian cells.

Author: Prendergast L, Hong E, Safina A, Poe D, and Gurova K
Subjects: Animals, Ataxia Telangiectasia Mutated Proteins metabolism, Cell Line, Cells, Cultured, Checkpoint Kinase 1 metabolism, Chromatin genetics, Chromatin metabolism, DNA, Single-Stranded genetics, DNA, Single-Stranded metabolism, DNA-Binding Proteins metabolism, High Mobility Group Proteins metabolism, Histone Chaperones metabolism, Humans, MCF-7 Cells, Mice, Knockout, Minichromosome Maintenance Proteins genetics, Minichromosome Maintenance Proteins metabolism, RNA Interference, Replication Protein A metabolism, Transcriptional Elongation Factors metabolism, DNA Damage, DNA Replication genetics, DNA-Binding Proteins genetics, High Mobility Group Proteins genetics, Histone Chaperones genetics, Transcriptional Elongation Factors genetics
Abstract: The histone chaperone FACT is upregulated during mammary tumorigenesis and necessary for the viability and growth of breast tumor cells. We established that only proliferating tumor cells are sensitive to FACT knockdown, suggesting that FACT functions during DNA replication in tumor cells but not in normal cells. We hypothesized that the basal level of replication stress defines the FACT dependence of cells. Using genetic and chemical tools, we demonstrated that FACT is needed to overcome replication stress. In the absence of FACT during replication stress, the MCM2-7 helicase dissociates from chromatin, resulting in the absence of ssDNA accumulation, RPA binding, and activation of the ATR/CHK1 checkpoint response. Without this response, stalled replication forks are not stabilized, and new origin firing cannot be prevented, leading to the accumulation of DNA damage and cell death. Thus, we propose a novel role for FACT as a factor preventing helicase dissociation from chromatin during replication stress.
Published: 2020
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41. Potent antileukemic activity of curaxin CBL0137 against MLL-rearranged leukemia.

Author: Somers K, Kosciolek A, Bongers A, El-Ayoubi A, Karsa M, Mayoh C, Wadham C, Middlemiss S, Neznanov N, Kees UR, Lock RB, Gudkov A, Sutton R, Gurova K, Haber M, Norris MD, and Henderson MJ
Subjects: Animals, Antineoplastic Agents therapeutic use, Apoptosis genetics, Carbazoles therapeutic use, Cell Line, Tumor, DNA-Binding Proteins genetics, Disease Models, Animal, Gene Expression Profiling, High Mobility Group Proteins genetics, Humans, Kaplan-Meier Estimate, Leukemia, Biphenotypic, Acute diagnosis, Leukemia, Biphenotypic, Acute drug therapy, Leukemia, Biphenotypic, Acute genetics, Leukemia, Biphenotypic, Acute mortality, Mice, Signal Transduction drug effects, Transcriptional Elongation Factors genetics, Transcriptome, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, Carbazoles pharmacology, Gene Rearrangement, Histone-Lysine N-Methyltransferase genetics, Myeloid-Lymphoid Leukemia Protein genetics
Abstract: Around 10% of acute leukemias harbor a rearrangement of the MLL/KMT2A gene, and the presence of this translocation results in a highly aggressive, therapy-resistant leukemia subtype with survival rates below 50%. There is a high unmet need to identify safer and more potent therapies for MLL-rearranged (MLL-r) leukemia that can be combined with established chemotherapeutics to decrease treatment-related toxicities. The curaxin, CBL0137, has demonstrated nongenotoxic anticancer and chemopotentiating effects in a number of preclinical cancer models and is currently in adult Phase I clinical trials for solid tumors and hematological malignancies. The aim of our study was to investigate whether CBL0137 has potential as a therapeutic and chemopotentiating compound in MLL-r leukemia through a comprehensive analysis of its efficacy in preclinical models of the disease. CBL0137 decreased the viability of a panel of MLL-r leukemia cell lines (n = 12) and xenograft cells derived from patients with MLL-r acute lymphoblastic leukemia (ALL, n = 3) in vitro with submicromolar IC50s. The small molecule drug was well-tolerated in vivo and significantly reduced leukemia burden in a subcutaneous MV4;11 MLL-r acute myeloid leukemia model and in patient-derived xenograft models of MLL-r ALL (n = 5). The in vivo efficacy of standard of care drugs used in remission induction for pediatric ALL was also potentiated by CBL0137. CBL0137 exerted its anticancer effect by trapping Facilitator of Chromatin Transcription (FACT) into chromatin, activating the p53 pathway and inducing an Interferon response. Our findings support further preclinical evaluation of CBL0137 as a new approach for the treatment of MLL-r leukemia., (© 2019 UICC.)
Published: 2020
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42. Curaxin CBL0137 has the potential to reverse HIV-1 latency.

Author: Jean MJ, Zhou D, Fiches G, Kong W, Huang H, Purmal A, Gurova K, Santoso NG, and Zhu J
Subjects: Cells, Cultured, Humans, Leukocytes, Mononuclear drug effects, Leukocytes, Mononuclear virology, Tumor Necrosis Factor-alpha metabolism, Carbazoles pharmacology, HIV Infections virology, HIV-1 physiology, Virus Activation drug effects, Virus Latency
Abstract: A cure for human immunodeficiency virus type-1 (HIV-1) has been hampered by the limitation of current combination antiretroviral therapy (cART) to address the latent reservoirs in HIV-1 patients. One strategy proposed to eradicate these reservoirs is the "shock and kill" approach, where latency-reversing agents (LRAs) are used to reactivate and promote viral cell death and/or immune killing of reactivated cells. Here, we report that curaxin CBL0137, an antitumor compound, can potentiate tumor necrosis factor-α-mediated reactivation of latently infected HIV-1cell lines. Additionally, the single use of CBL0137 is sufficient to reactivate HIV-1 latent reservoirs in peripheral mononuclear cells (PBMCs) isolated from HIV-1 positive, cART-treated, aviremic patients. Thus, CBL0137 possesses capabilities as a LRA and could be considered for the "shock and kill" approach., (© 2019 Wiley Periodicals, Inc.)
Published: 2019
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43. Structure and function of the histone chaperone FACT - Resolving FACTual issues.

Author: Gurova K, Chang HW, Valieva ME, Sandlesh P, and Studitsky VM
Abstract: FAcilitates Chromatin Transcription (FACT) has been considered essential for transcription through chromatin mostly based on cell-free experiments. However, FACT inactivation in cells does not cause a significant reduction in transcription. Moreover, not all mammalian cells require FACT for viability. Here we synthesize information from different organisms to reveal the core function(s) of FACT and propose a model that reconciles the cell-free and cell-based observations. We describe FACT structure and nucleosomal interactions, and their roles in FACT-dependent transcription, replication and repair. The variable requirements for FACT among different tumor and non-tumor cells suggest that various FACT-dependent processes have significantly different levels of relative importance in different eukaryotic cells. We propose that the stability of chromatin, which might vary among different cell types, dictates these diverse requirements for FACT to support cell viability. Since tumor cells are among the most sensitive to FACT inhibition, this vulnerability could be exploited for cancer treatment., (Copyright © 2018. Published by Elsevier B.V.)
Published: 2018
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44. TRAIN (Transcription of Repeats Activates INterferon) in response to chromatin destabilization induced by small molecules in mammalian cells.

Author: Leonova K, Safina A, Nesher E, Sandlesh P, Pratt R, Burkhart C, Lipchick B, Gitlin I, Frangou C, Koman I, Wang J, Kirsanov K, Yakubovskaya MG, Gudkov AV, and Gurova K
Subjects: Animals, Antineoplastic Agents metabolism, Cells, Cultured, Histone Deacetylase Inhibitors metabolism, Humans, Mice, Chromatin metabolism, DNA Methylation, Genomic Instability, Interferons metabolism, Transcription, Genetic
Abstract: Cellular responses to the loss of genomic stability are well-established, while how mammalian cells respond to chromatin destabilization is largely unknown. We previously found that DNA demethylation on p53-deficient background leads to transcription of repetitive heterochromatin elements, followed by an interferon response, a phenomenon we named TRAIN (Transcription of Repeats Activates INterferon). Here, we report that curaxin, an anticancer small molecule, destabilizing nucleosomes via disruption of histone/DNA interactions, also induces TRAIN. Furthermore, curaxin inhibits oncogene-induced transformation and tumor growth in mice in an interferon-dependent manner, suggesting that anticancer activity of curaxin, previously attributed to p53-activation and NF-kappaB-inhibition, may also involve induction of interferon response to epigenetic derepression of the cellular 'repeatome'. Moreover, we observed that another type of drugs decondensing chromatin, HDAC inhibitor, also induces TRAIN. Thus, we proposed that TRAIN may be one of the mechanisms ensuring epigenetic integrity of mammalian cells via elimination of cells with desilenced chromatin., Competing Interests: KL, AS, EN, PS, RP, CB, BL, IG, CF, IK, JW, KK, MY, AG, KG No competing interests declared, (© 2018, Leonova et al.)
Published: 2018
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45. Curaxin CBL0100 Blocks HIV-1 Replication and Reactivation through Inhibition of Viral Transcriptional Elongation.

Author: Jean MJ, Hayashi T, Huang H, Brennan J, Simpson S, Purmal A, Gurova K, Keefer MC, Kobie JJ, Santoso NG, and Zhu J
Abstract: Despite combination antiretroviral therapy (cART), acquired immunodeficiency syndrome (AIDS), predominantly caused by the human immunodeficiency virus type 1 (HIV-1), remains incurable. The barrier to a cure lies in the virus' ability to establish a latent infection in HIV/AIDS patients. Unsurprisingly, efforts for a sterilizing cure have focused on the "shock and kill" strategy using latency-reversing agents (LRAs) to complement cART in order to eliminate these latent reservoirs. However, this method faces numerous challenges. Recently, the "block and lock" strategy has been proposed. It aims to reinforce a deep state of latency and prevent sporadic reactivation ("blip") of HIV-1 using latency-promoting agents (LPAs) for a functional cure. Our studies of curaxin 100 (CBL0100), a small-molecule targeting the facilitates chromatin transcription (FACT) complex, show that it blocks both HIV-1 replication and reactivation in in vitro and ex vivo models of HIV-1. Mechanistic investigation elucidated that CBL0100 preferentially targets HIV-1 transcriptional elongation and decreases the occupancy of RNA Polymerase II (Pol II) and FACT at the HIV-1 promoter region. In conclusion, CBL0100 is a newly identified inhibitor of HIV-1 transcription that can be used as an LPA in the "block and lock" cure strategy.
Published: 2017
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46. Level of FACT defines the transcriptional landscape and aggressive phenotype of breast cancer cells.

Author: Fleyshman D, Prendergast L, Safina A, Paszkiewicz G, Commane M, Morgan K, Attwood K, and Gurova K
Subjects: Biomarkers, Tumor, Blotting, Western, Breast Neoplasms metabolism, Cell Line, Tumor, DNA-Binding Proteins metabolism, Female, Flow Cytometry, High Mobility Group Proteins metabolism, Humans, Oligonucleotide Array Sequence Analysis, Phenotype, Reverse Transcriptase Polymerase Chain Reaction, Transcriptional Elongation Factors metabolism, Breast Neoplasms genetics, Breast Neoplasms pathology, DNA-Binding Proteins genetics, High Mobility Group Proteins genetics, Transcriptional Elongation Factors genetics
Abstract: Although breast cancer (BrCa) may be detected at an early stage, there is a shortage of markers that predict tumor aggressiveness and a lack of targeted therapies. Histone chaperone FACT, expressed in a limited number of normal cells, is overexpressed in different types of cancer, including BrCa. Recently, we found that FACT expression in BrCa correlates with markers of aggressive BrCa, which prompted us to explore the consequences of FACT inhibition in BrCa cells with varying levels of FACT.FACT inhibition using a small molecule or shRNA caused reduced growth and viability of all BrCa cells tested. Phenotypic changes were more severe in "high- FACT" cells (death or growth arrest) than in "low-FACT" cells (decreased proliferation). Though inhibition had no effect on the rate of general transcription, expression of individual genes was changed in a cell-specific manner. Initially distinct transcriptional profiles of BrCa cells became similar upon equalizing FACT expression. In "high-FACT" cells, FACT supports expression of genes involved in the regulation of cell cycle, DNA replication, maintenance of an undifferentiated cell state and regulated by the activity of several proto-oncogenes. In "low-FACT" cells, the presence of FACT reduces expression of genes encoding enzymes of steroid metabolism that are characteristic of differentiated mammary epithelia.Thus, we propose that FACT is both a marker and a target of aggressive BrCa cells, whose inhibition results in the death of BrCa or convertion of them to a less aggressive subtype.
Published: 2017
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47. FACT is a sensor of DNA torsional stress in eukaryotic cells.

Author: Safina A, Cheney P, Pal M, Brodsky L, Ivanov A, Kirsanov K, Lesovaya E, Naberezhnov D, Nesher E, Koman I, Wang D, Wang J, Yakubovskaya M, Winkler D, and Gurova K
Subjects: Cell Line, Chromatin genetics, Chromatin metabolism, Chromatin Assembly and Disassembly, Chromosomal Proteins, Non-Histone chemistry, Chromosomal Proteins, Non-Histone metabolism, DNA metabolism, Humans, Microsatellite Repeats, Models, Biological, Nucleosomes genetics, Nucleosomes metabolism, Protein Binding, Protein Subunits, Transcription Factors chemistry, Transcription Factors metabolism, DNA chemistry, DNA genetics, DNA-Binding Proteins metabolism, Eukaryotic Cells metabolism, Nucleic Acid Conformation
Abstract: Transitions of B-DNA to alternative DNA structures (ADS) can be triggered by negative torsional strain, which occurs during replication and transcription, and may lead to genomic instability. However, how ADS are recognized in cells is unclear. We found that the binding of candidate anticancer drug, curaxin, to cellular DNA results in uncoiling of nucleosomal DNA, accumulation of negative supercoiling and conversion of multiple regions of genomic DNA into left-handed Z-form. Histone chaperone FACT binds rapidly to the same regions via the SSRP1 subunit in curaxin-treated cells. In vitro binding of purified SSRP1 or its isolated CID domain to a methylated DNA fragment containing alternating purine/pyrimidines, which is prone to Z-DNA transition, is much stronger than to other types of DNA. We propose that FACT can recognize and bind Z-DNA or DNA in transition from a B to Z form. Binding of FACT to these genomic regions triggers a p53 response. Furthermore, FACT has been shown to bind to other types of ADS through a different structural domain, which also leads to p53 activation. Thus, we propose that FACT acts as a sensor of ADS formation in cells. Recognition of ADS by FACT followed by a p53 response may explain the role of FACT in DNA damage prevention., (© The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.)
Published: 2017
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48. Novel synthetic cyclic integrin αvβ3 binding peptide ALOS4: Antitumor activity in mouse melanoma models.

Author: Yacobovich S, Tuchinsky L, Kirby M, Kardash T, Agranyoni O, Nesher E, Redko B, Gellerman G, Tobi D, Gurova K, Koman I, Ashur Fabian O, and Pinhasov A
Subjects: Animals, Apoptosis drug effects, Cell Movement drug effects, Cell Proliferation drug effects, Lung Neoplasms secondary, Melanoma, Experimental pathology, Mice, Mice, Inbred C57BL, Peptide Library, Tumor Cells, Cultured, Integrin alphaVbeta3 metabolism, Lung Neoplasms prevention & control, Melanoma, Experimental prevention & control, Peptides, Cyclic pharmacology
Abstract: ALOS4, a unique synthetic cyclic peptide without resemblance to known integrin ligand sequences, was discovered through repeated biopanning with pIII phage expressing a disulfide-constrained nonapeptide library. Binding assays using a FITC-labeled analogue demonstrated selective binding to immobilized αvβ3 and a lack of significant binding to other common proteins, such as bovine serum albumin and collagen. In B16F10 cell cultures, ALOS4 treatment at 72 h inhibited cell migration (30%) and adhesion (up to 67%). Immunofluorescent imaging an ALOS4-FITC analogue with B16F10 cells demonstrated rapid cell surface binding, and uptake and localization in the cytoplasm. Daily injections of ALOS4 (0.1, 0.3 or 0.5 mg/kg i.p.) to mice inoculated with B16F10 mouse melanoma cells in two different cancer models, metastatic and subcutaneous tumor, resulted in reduction of lung tumor count (metastatic) and tumor mass (subcutaneous) and increased survival of animals monitored to 45 and 60 days, respectively. Examination of cellular activity indicated that ALOS4 produces inhibition of cell migration and adhesion in a concentration-dependent manner. Collectively, these results suggest that ALOS4 is a structurally-unique selective αvβ3 integrin ligand with potential anti-metastatic activity.
Published: 2016
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49. ARTIK-52 induces replication-dependent DNA damage and p53 activation exclusively in cells of prostate and breast cancer origin.

Author: Fleyshman D, Cheney P, Ströse A, Mudambi S, Safina A, Commane M, Purmal A, Morgan K, Wang NJ, Gray J, Spellman PT, Issaeva N, and Gurova K
Subjects: Blotting, Northern, Breast Neoplasms metabolism, Breast Neoplasms pathology, Carbazoles chemistry, Cell Line, Tumor, Comet Assay, DNA Replication drug effects, Female, Humans, MCF-7 Cells, Male, Microscopy, Fluorescence, Prostate pathology, Prostatic Neoplasms metabolism, Prostatic Neoplasms pathology, RNA Interference, RNA, Messenger metabolism, RNA, Small Interfering metabolism, Real-Time Polymerase Chain Reaction, Receptors, Androgen chemistry, Receptors, Androgen genetics, Receptors, Androgen metabolism, Androgen Receptor Antagonists pharmacology, Carbazoles toxicity, DNA Damage drug effects, Prostate metabolism, Tumor Suppressor Protein p53 metabolism
Abstract: The realization, that the androgen receptor (AR) is essential for prostate cancer (PC) even after relapse following androgen deprivation therapy motivated the search for novel types of AR inhibitors. We proposed that targeting AR expression versus its function would work in cells having either wild type or mutant AR as well as be independent of androgen synthesis pathways. Previously, using a phenotypic screen in androgen-independent PC cells we identified a small molecule inhibitor of AR, ARTIK-52. Treatment with ARTIK-52 caused the loss of AR protein and death of AR-positive, but not AR-negative, PC cells. Here we present data that ARTIK-52 induces degradation of AR mRNA through a mechanism that we were unable to establish. However, we found that ARTIK-52 is toxic to breast cancer (BC) cells expressing AR, although they were not sensitive to AR knockdown, suggesting an AR-independent mechanism of toxicity. Using different approaches we detected that ARTIK-52 induces replication-dependent double strand DNA breaks exclusively in cancer cells of prostate and breast origin, while not causing DNA damage, or any toxicity, in normal cells, as well as in non-PC and non-BC tumor cells, independent of their proliferation status. This amazing specificity, combined with such a basic mechanism of toxicity, makes ARTIK-52 a potentially useful tool to discover novel attractive targets for the treatment of BC and PC. Thus, phenotypic screening allowed us to identify a compound, whose properties cannot be predicted based on existing knowledge and moreover, uncover a barely known link between AR and DNA damage response in PC and BC epithelial cells.
Published: 2016
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50. FACT Proteins, SUPT16H and SSRP1, Are Transcriptional Suppressors of HIV-1 and HTLV-1 That Facilitate Viral Latency.

Author: Huang H, Santoso N, Power D, Simpson S, Dieringer M, Miao H, Gurova K, Giam CZ, Elledge SJ, and Zhu J
Subjects: CD4-Positive T-Lymphocytes physiology, CD4-Positive T-Lymphocytes virology, Cell Cycle Proteins antagonists & inhibitors, Cell Cycle Proteins genetics, Cell Line, Cyclin T physiology, DNA-Binding Proteins antagonists & inhibitors, DNA-Binding Proteins genetics, HEK293 Cells, HIV Long Terminal Repeat, HIV-1 genetics, High Mobility Group Proteins antagonists & inhibitors, High Mobility Group Proteins genetics, Host-Pathogen Interactions genetics, Host-Pathogen Interactions physiology, Human T-lymphotropic virus 1 genetics, Humans, Models, Biological, Positive Transcriptional Elongation Factor B physiology, Promoter Regions, Genetic, RNA Interference, Transcription Factors antagonists & inhibitors, Transcription Factors genetics, Transcriptional Elongation Factors antagonists & inhibitors, Transcriptional Elongation Factors genetics, Virus Latency genetics, Cell Cycle Proteins physiology, DNA-Binding Proteins physiology, HIV-1 physiology, High Mobility Group Proteins physiology, Human T-lymphotropic virus 1 physiology, Transcription Factors physiology, Transcriptional Elongation Factors physiology, Virus Latency physiology
Abstract: Our functional genomic RNAi screens have identified the protein components of the FACT (facilitates chromatin transcription) complex, SUPT16H and SSRP1, as top host factors that negatively regulate HIV-1 replication. FACT interacts specifically with histones H2A/H2B to affect assembly and disassembly of nucleosomes, as well as transcription elongation. We further investigated the suppressive role of FACT proteins in HIV-1 transcription. First, depletion of SUPT16H or SSRP1 protein enhances Tat-mediated HIV-1 LTR (long terminal repeat) promoter activity. Second, HIV-1 Tat interacts with SUPT16H but not SSRP1 protein. However, both SUPT16H and SSRP1 are recruited to LTR promoter. Third, the presence of SUPT16H interferes with the association of Cyclin T1 (CCNT1), a subunit of P-TEFb, with the Tat-LTR axis. Removing inhibitory mechanisms to permit HIV-1 transcription is an initial and key regulatory step to reverse post-integrated latent HIV-1 proviruses for purging of reservoir cells. We therefore evaluated the role of FACT proteins in HIV-1 latency and reactivation. Depletion of SUPT16H or SSRP1 protein affects both HIV-1 transcriptional initiation and elongation and spontaneously reverses latent HIV-1 in U1/HIV and J-LAT cells. Similar effects were observed with a primary CD4+ T cell model of HIV-1 latency. FACT proteins also interfere with HTLV-1 Tax-LTR-mediated transcription and viral latency, indicating that they may act as general transcriptional suppressors for retroviruses. We conclude that FACT proteins SUPT16H and SSRP1 play a key role in suppressing HIV-1 transcription and promoting viral latency, which may serve as promising gene targets for developing novel HIV-1 latency-reversing agents., (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)
Published: 2015
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