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21 results on '"Bridge, Katherine S."'

1. PU.1 eviction at lymphocyte-specific chromatin domains mediates glucocorticoid response in acute lymphoblastic leukemia

Author

Beck, Dominik, Cao, Honghui, Tian, Feng, Huang, Yizhou, Jiang, Miao, Zhao, Han, Tai, Xiaolu, Xu, Wenqian, Kosasih, Hansen J., Kealy, David J., Zhao, Weiye, Taylor, Samuel J., Couttas, Timothy A., Song, Gaoxian, Chacon-Fajardo, Diego, Walia, Yashna, Wang, Meng, Dowle, Adam A., Holding, Andrew N., Bridge, Katherine S., Zhang, Chao, Wang, Jin, Mi, Jian-Qing, Lock, Richard B., de Bock, Charles E., and Jing, Duohui

Published
2024
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3. Hypoxia-induced epigenetic regulation of breast cancer progression and the tumour microenvironment.

Author

Capatina, Alina L., Malcolm, Jodie R., Stenning, Jack, Moore, Rachael L., Bridge, Katherine S., Brackenbury, William J., and Holding, Andrew N.

Subjects
TRIPLE-negative breast cancer, BREAST cancer, GENE expression, POST-translational modification, PROGNOSIS
Abstract

The events that control breast cancer progression and metastasis are complex and intertwined. Hypoxia plays a key role both in oncogenic transformation and in fueling the metastatic potential of breast cancer cells. Here we review the impact of hypoxia on epigenetic regulation of breast cancer, by interfering with multiple aspects of the tumour microenvironment. The co-dependent relationship between oxygen depletion and metabolic shift to aerobic glycolysis impacts on a range of enzymes and metabolites available in the cell, promoting posttranslational modifications of histones and chromatin, and changing the gene expression landscape to facilitate tumour development. Hormone signalling, particularly through ERa, is also tightly regulated by hypoxic exposure, with HIF-1a expression being a prognostic marker for therapeutic resistance in ER+ breast cancers. This highlights the strong need to understand the hypoxia-endocrine signalling axis and exploit it as a therapeutic target. Furthermore, hypoxia has been shown to enhance metastasis in TNBC cells, as well as promoting resistance to taxanes, radiotherapy and even immunotherapy throughmicroRNA regulation and changes in histone packaging. Finally, several other mediators of the hypoxic response are discussed. We highlight a link between ionic dysregulation and hypoxia signalling, indicating a potential connection between HIF-1a and tumouralNa+ accumulation whichwould be worth further exploration;we present the role of Ca2+ in mediating hypoxic adaptation via chromatin remodelling, transcription factor recruitment and changes in signalling pathways; and we briefly summarise some of the findings regarding vesicle secretion and paracrine induced epigenetic reprogramming upon hypoxic exposure in breast cancer. By summarising these observations, this article highlights the heterogeneity of breast cancers, presenting a series of pathways with potential for therapeutic applications. [ABSTRACT FROM AUTHOR]

Published
2024
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4. ZMIZ1 enhances ERα-dependent expression of E2F2 in breast cancer

Author

Zhao, Weiye, primary, Rose, Susanna F, additional, Blake, Ryan, additional, Godicelj, Aňze, additional, Cullen, Amy E, additional, Stenning, Jack, additional, Beevors, Lucy, additional, Gehrung, Marcel, additional, Kumar, Sanjeev, additional, Kishore, Kamal, additional, Sawle, Ashley, additional, Eldridge, Matthew, additional, Giorgi, Federico M, additional, Bridge, Katherine S, additional, Markowetz, Florian, additional, and Holding, Andrew N, additional

Published
2024
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6. Regulation of HIF-l and the hypoxic response by the tumour suppressor LIMDl and LIM domains-containing proteins

Author

Bridge, Katherine S.

Subjects
616.994
Abstract

In order to survive in a given environment, adequate levels of oxygen are required throughout cells and tissues, as defined by cellular function and tissue type. Rapid reaction and adaption of a cell or tissue to low p02 (hypoxia) can enable it to remain viable, thus reducing potential damage to the organism. The hypoxic response signalling pathway is activated by hypoxia inducible factors (HIFs); these transcription factors activate genes whose products enable the cell to adapt to hypoxic conditions, including vascular endothelial growth factor (VEGF) and erythropoietin (EPO) . Under normal oxygen conditions (normoxia), the HIF-la subunit is rapidly degraded as a result of hydroxylation by the prolyl hydroxylase domain proteins (PHDl-3) and subsequent binding of the von Hippel-Lindau protein (VHL), which induces ubiquitination and degradation of HIF-la by the 265 proteasome. Data presented in this thesis identify the LlM domains-containing tumour suppressor gene product LlMD1, as well as other members of the ZYX class of LlM domain proteins, as regulators of HIF-l and the hypoxic response. LlMDl interacts with the PHDs and VHL at distinct sites to facilitate efficient HIF-la degradation by bringing the hydroxylase and ubiquitinase enzymes into close proximity. LlMDl enhances HIF-la degradation via the oxygen dependent degradation (ODD) domain and represses HIF-l transcriptional activity; these effects are dependent upon the ability of LlMDl to engage PHD2/VHL. In addition to LlMD1, ZYX class members Ajuba and WTIP also interact with PHD1/3 and VHL, and Ajuba confers enhanced HIF-la protein degradation. Preliminary evidence suggests Zyxin, TRIP6 and LPP, also members of the ZYX class, act as positive regulators of HIF-l, enhancing HIF-la protein stability and HIF-l transcriptional activity. This thesis therefore identifies LlMDl and implicates the ZYX class of LlM domain proteins as a unique family of protein regulators of HIF-l and the hypoxic response.

Published
2013

9. A HIF–LIMD1 negative feedback mechanism mitigates the pro‐tumorigenic effects of hypoxia

Author

Foxler, Daniel E, Bridge, Katherine S, Foster, John G, Grevitt, Paul, Curry, Sean, Shah, Kunal M, Davidson, Kathryn M, Nagano, Ai, Gadaleta, Emanuela, Rhys, Hefin I, Kennedy, Paul T, Hermida, Miguel A, Chang, Ting‐Yu, Shaw, Peter E, Reynolds, Louise E, McKay, Tristan R, Wang, Hsei‐Wei, Ribeiro, Paulo S, Plevin, Michael J, Lagos, Dimitris, Lemoine, Nicholas R, Rajan, Prabhakar, Graham, Trevor A, Chelala, Claude, Hodivala‐Dilke, Kairbaan M, Spendlove, Ian, and Sharp, Tyson V

Published
2018
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10. Hematopoietic stem cells retain functional potential and molecular identity in hibernation cultures

Author

Oedekoven, Caroline A., primary, Belmonte, Miriam, additional, Bode, Daniel, additional, Hamey, Fiona K., additional, Shepherd, Mairi S., additional, Che, James Lok Chi, additional, Boyd, Grace, additional, McDonald, Craig, additional, Belluschi, Serena, additional, Diamanti, Evangelia, additional, Bastos, Hugo P., additional, Bridge, Katherine S., additional, Göttgens, Berthold, additional, Laurenti, Elisa, additional, and Kent, David G., additional

Published
2021
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12. Targeted therapy for LIMD1-deficient non-small cell lung cancer subtypes

Author

Davidson, Kathryn, primary, Grevitt, Paul, additional, Contreras G., Maria F., additional, Bridge, Katherine S., additional, Hermida, Miguel, additional, Shah, Kunal M., additional, Mardakheh, Faraz K, additional, Stubbs, Mark, additional, Clarke, Paul A., additional, Burke, Rosemary, additional, Casado-Izquierdo, Pedro, additional, Cutillas, Pedro R., additional, Martin, Sarah A., additional, and Sharp, Tyson V., additional

Published
2021
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13. S6K2-mediated regulation of TRBP as a determinant of miRNA expression in human primary lymphatic endothelial cells

Author

Warner, Matthew J, Bridge, Katherine S, Hewitson, James P, Hodgkinson, Michael R, Heyam, Alex, Massa, Bailey C, Haslam, Jessica C, Chatzifrangkeskou, Maria, Evans, Gareth J O, Plevin, Michael J, Sharp, Tyson V, and Lagos, Dimitris

Subjects
MicroRNAs, Gene Expression Regulation, Ribosomal Protein S6 Kinases, Angiopoietin-1, RNA, Endothelial Cells, Humans, RNA-Binding Proteins, Protein Interaction Domains and Motifs, Phosphorylation, Cells, Cultured, Cell Line
Abstract

MicroRNAs (miRNAs) are short non-coding RNAs that silence mRNAs. They are generated following transcription and cleavage by the DROSHA/DGCR8 and DICER/TRBP/PACT complexes. Although it is known that components of the miRNA biogenesis machinery can be phosphorylated, it remains poorly understood how these events become engaged during physiological cellular activation. We demonstrate that S6 kinases can phosphorylate the extended C-terminal domain of TRBP and interact with TRBP in situ in primary cells. TRBP serines 283/286 are essential for S6K-mediated TRBP phosphorylation, optimal expression of TRBP, and the S6K-TRBP interaction in human primary cells. We demonstrate the functional relevance of this interaction in primary human dermal lymphatic endothelial cells (HDLECs). Angiopoietin-1 (ANG1) can augment miRNA biogenesis in HDLECs through enhancing TRBP phosphorylation and expression in an S6K2-dependent manner. We propose that the S6K2/TRBP node controls miRNA biogenesis in HDLECs and provides a molecular link between the mTOR pathway and the miRNA biogenesis machinery.

Published
2016

14. In Breast Cancer ZMIZ1 Co-Regulates E2F2 as Part of the Estrogen Receptor-Mediated Cell-Cycle Response

Author

Zhao, Weiye, primary, Rose, Susanna F, additional, Blake, Ryan, additional, Godicelj, Anže, additional, Cullen, Amy E, additional, Stenning, Jack, additional, Beevors, Lucy, additional, Gehrung, Marcel, additional, Kumar, Sanjeev, additional, Kishore, Kamal, additional, Sawle, Ashley, additional, Eldridge, Matthew, additional, Giorgi, Federico M, additional, Bridge, Katherine S, additional, Markowetz, Florian, additional, and Holding, Andrew N, additional

Published
2019
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15. A HIF – LIMD 1 negative feedback mechanism mitigates the pro‐tumorigenic effects of hypoxia

Author

Foxler, Daniel E, primary, Bridge, Katherine S, additional, Foster, John G, additional, Grevitt, Paul, additional, Curry, Sean, additional, Shah, Kunal M, additional, Davidson, Kathryn M, additional, Nagano, Ai, additional, Gadaleta, Emanuela, additional, Rhys, Hefin I, additional, Kennedy, Paul T, additional, Hermida, Miguel A, additional, Chang, Ting‐Yu, additional, Shaw, Peter E, additional, Reynolds, Louise E, additional, McKay, Tristan R, additional, Wang, Hsei‐Wei, additional, Ribeiro, Paulo S, additional, Plevin, Michael J, additional, Lagos, Dimitris, additional, Lemoine, Nicholas R, additional, Rajan, Prabhakar, additional, Graham, Trevor A, additional, Chelala, Claude, additional, Hodivala‐Dilke, Kairbaan M, additional, Spendlove, Ian, additional, and Sharp, Tyson V, additional

Published
2018
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16. Argonaute Utilization for miRNA Silencing Is Determined by Phosphorylation-Dependent Recruitment of LIM-Domain-Containing Proteins

Author

Bridge, Katherine S., primary, Shah, Kunal M., additional, Li, Yigen, additional, Foxler, Daniel E., additional, Wong, Sybil C.K., additional, Miller, Duncan C., additional, Davidson, Kathryn M., additional, Foster, John G., additional, Rose, Ruth, additional, Hodgkinson, Michael R., additional, Ribeiro, Paulo S., additional, Aboobaker, A. Aziz, additional, Yashiro, Kenta, additional, Wang, Xiaozhong, additional, Graves, Paul R., additional, Plevin, Michael J., additional, Lagos, Dimitris, additional, and Sharp, Tyson V., additional

Published
2017
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17. Aberrant Splicing of MBD1Reshapes the Epigenome to Drive Convergent Myeloerythroid Defects in MDS

Author

Chen, He Tian (Tony) Tony, Joshi, Pratik, Tsao, Emily, Xu, Joshua, Jahangiri, Soheil, Mo, Yulin, Kealy, David, Gowlett-Park, Dylan, Czibere, Katarina, Misura, Alexandra, Bigun, Olga, Sasso, Renato, Chadwick, Dianne, Usta, Sila, Khazaee, Tina, Chow, Signy, Tsui, Hubert, Minden, Mark D., Bridge, Katherine S, Zheng, Gang, and Hope, Kristin J.

Abstract

Splicing defects are a characteristic feature of myelodysplastic syndromes (MDS) and typically associate with specific recurrent splicing factor mutations. However, a subset of transcripts exhibit abnormal splicing regardless of mutational background, occurring even in the absence of splicing-related mutations. These shared splicing events likely include common underlying drivers of MDS hematopoietic defects, yet the functions of the resulting transcripts remain unknown. We identified a long isoform of Methyl-CpG-Binding Domain 1 ( MBD1) as the product of one such mutation-independent splicing event. To understand whether altered MBD1splicing contributes to hematopoietic dysfunction, we overexpressed isoforms of MBD1in cord blood CD34+ cells and found that the MDS-associated full-length isoform (MBD1-L), containing MBD1's 3rd CXXC domain, impaired erythroid differentiation by stalling cell cycling and promoting apoptosis. In contrast, the MBD1-ΔCXXC3 isoform (MBD1-S), preferentially produced in healthy cells, did not induce these defects. Recapitulating these findings, the MBD1-L isoform uniquely impaired reconstitution capacity in vivo, particularly in the erythroid and myeloid lineages, and in addition produced an enrichment of the MDS transcriptomic signature on RNA-seq profiling.

Published
2023
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20. The LIMD1 protein bridges an association between the prolyl hydroxylases and VHL to repress HIF-1 activity

Author

Foxler, Daniel E., primary, Bridge, Katherine S., additional, James, Victoria, additional, Webb, Thomas M., additional, Mee, Maureen, additional, Wong, Sybil C. K., additional, Feng, Yunfeng, additional, Constantin-Teodosiu, Dumitru, additional, Petursdottir, Thorgunnur Eyfjord, additional, Bjornsson, Johannes, additional, Ingvarsson, Sigurdur, additional, Ratcliffe, Peter J., additional, Longmore, Gregory D., additional, and Sharp, Tyson V., additional

Published
2012
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21. Physioxia improves the selectivity of hematopoietic stem cell expansion cultures

Author

Gottgens, Berthold, Igarashi, Kyomi J [0000-0002-4352-3835], Kucinski, Iwo [0000-0002-9385-0359], Tan, Tze-Kai [0000-0002-7359-5303], Kealy, David [0000-0001-9246-8134], Bhadury, Joydeep [0000-0002-4333-9974], Hsu, Ian [0000-0002-1648-5060], Ho, Pui Yan [0000-0003-0728-4352], Bridge, Katherine S [0000-0003-1516-1459], Nakauchi, Hiromitsu [0000-0002-8122-2566], Wilkinson, Adam C [0000-0001-7406-0151], and Apollo - University of Cambridge Repository

Subjects
Mice, Hematopoietic Stem Cell Transplantation, Animals, Transplantation, Homologous, Graft vs Host Disease, Hematopoietic Stem Cells
Abstract

Hematopoietic stem cells (HSCs) are a rare hematopoietic cell type that can entirely reconstitute the blood and immune systems following transplantation. Allogeneic HSC transplantation (HSCT) is used clinically as a curative therapy for a range of hematolymphoid diseases, but remains a high-risk therapy due to potential side effects including poor graft function and graft 6 vs-host disease (GvHD). Ex vivo HSC expansion has been suggested as an approach to improve hematopoietic reconstitution from low-cell dose grafts. Here, we demonstrate that we can improve the selectivity of polyvinyl alcohol (PVA)-based mouse HSC cultures through the use of physioxic culture conditions. Single-cell transcriptomic analysis confirmed inhibition of lineage-committed progenitor cells in physioxic cultures. Long-term physioxic expansion also afforded culture-based ex vivo HSC selection from whole bone marrow, spleen, and embryonic tissues. Furthermore, we provide evidence that HSC-selective ex vivo cultures deplete GvHD 13 causing T cells and that this approach can be combined with genotoxic-free antibody-based conditioning HSCT approaches. Our results offer a simple approach to improve PVA-based HSC cultures and the underlying molecular phenotype, as well as highlight the potential translational implications of selective HSC expansion systems for allogeneic HSCT.

Published
2023

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