![Trevor Dale](https://profiles-cardiff.imgix.net/attachments/990?w=200&h=200&auto=format&crop=faces&fit=crop&q=90")
Yr Athro Trevor Dale
Pennaeth Is-adran Biowyddorau Moleciwlaidd
Ysgol y Biowyddorau
- DaleTC@caerdydd.ac.uk
- +44 29208 74652
- Adeilad Syr Martin Evans, Ystafell E3.08, Rhodfa'r Amgueddfa, Caerdydd, CF10 3AX
Trosolwyg
Mae'r diddordeb gwyddonol hirdymor yn fy ngrŵp yn y mecanweithiau y mae nanoraddfa yn newid ar y lefel biocemegol (ee ffurfio cyfadeiladau protein) yn lledaenu trwy hierarchaethau graddfa ddilyniannol; intracellular, cellular, rhyng-gellog, meinwe ac organ.
Mae gwaith blaenorol wedi astudio sut mae newidiadau ym biocemeg llwybr signalau Wnt yn lledaenu trwy newidiadau i fioleg celloedd a meinwe sy'n arwain at ganser. Er enghraifft, mae'r gwaith hwn wedi cynnwys:
1. Biocemeg cydrannau llwybr Wnt fel y kinase GSK-3
2. Adnabod rheoleiddwyr Wnt newydd trwy cDNA, siRNA trwybwn uchel a sgrinio cyffuriau.
3. Y dadansoddiad o signalau Wnt arferol ac oncogenic gan ddefnyddio modelau murin a systemau diwylliant organoid 3D.
4. Colli y gwrth-oncogenes Axin mewn canser yr afu.
Mae'r gwaith presennol yn mynd i gyfeiriad newydd drwy gymhwyso egwyddorion sefydliad hierarchaidd i beirianneg deunyddiau biolegol newydd. Mae ffocws penodol ar gynhyrchu deunyddiau y gellir eu defnyddio i ddal CO2 i frwydro yn erbyn newid yn yr hinsawdd.
Mae ymchwil yn y grŵp wedi arwain at sefydlu dau gwmni deillio allan.
Rolau
Arweinydd Tîm Academaidd
Aelod o'r Sefydliad Bôn-gelloedd Canser Ewropeaidd
https://www.cardiff.ac.uk/cancer-stem-cell
Cyhoeddiad
2023
- Moore, J. W., Dale, T. C. and Woolley, T. E. 2023. Modelling polarity-driven laminar patterns in bilayer tissues with mixed signalling mechanisms. SIAM Journal on Applied Dynamical Systems 22(4), pp. 2945-2990. (10.1137/22M1522565)
2022
- Moore, J. W., Dale, T. C. and Woolley, T. E. 2022. Polarity driven laminar pattern formation by lateral-inhibition in 2D and 3D bilayer geometries. IMA Journal of Applied Mathematics 87(4), pp. 568-606.
- Engel, R. M. et al. 2022. Modeling colorectal cancer: A bio-resource of 50 patient-derived organoid lines. Journal of Gastroenterology and Hepatology 37(5), pp. 898-907. (10.1111/jgh.15818)
2021
- Moore, J. W., Lau, Z., Kaouri, K., Dale, T. C. and Woolley, T. E. 2021. A general computational framework for COVID-19 modelling with applications to testing varied interventions in education environments. COVID 1(4), pp. 674-703. (10.3390/covid1040055)
- Pope, I. et al. 2021. Identifying subpopulations in multicellular systems by quantitative chemical imaging using label-free hyperspectral CARS microscopy. Analyst 146(7), pp. 2277-2291. (10.1039/D0AN02381G)
2020
- Badder, L. M. et al. 2020. 3D imaging of colorectal cancer organoids identifies responses to Tankyrase inhibitors. PLoS ONE 15(8), article number: e0235319. (10.1371/journal.pone.0235319)
- Valle-Encinas, E. and Dale, T. C. 2020. Wnt ligand and receptor patterning in the liver. Current Opinion in Cell Biology 62, pp. 17-25. (10.1016/j.ceb.2019.07.014)
2019
- Young, R. M., Ewan, K. B., Ferrer, V. P., Allende, M. L., Godovac-Zimmermann, J., Dale, T. C. and Wilson, S. W. 2019. Developmentally regulated Tcf7l2 splice variants mediate transcriptional repressor functions during eye formation. eLife 8, article number: e51447. (10.7554/eLife.51447)
2018
- Pope, I. et al. 2018. Coherent Raman Scattering microscopy: technology developments and biological applications. Presented at: 20th International Conference on Transparent Optical Networks (ICTON), Bucharest, Romania, 1-5 Jul 201820th International Conference on Transparent Optical Networks (ICTON). IEEE, (10.1109/ICTON.2018.8473706)
2017
- Dietrich, L. et al. 2017. Cell permeable stapled peptide inhibitor of Wnt signaling that targets β-catenin protein‒protein interactions. Cell Chemical Biology 24(8), pp. 958-968., article number: e5. (10.1016/j.chembiol.2017.06.013)
- Carotenuto, P. et al. 2017. Wnt signalling modulates transcribed-ultraconserved regions in hepatobiliary cancers. Gut 66(7), pp. 1268-1277. (10.1136/gutjnl-2016-312278)
- Kay, S. K. et al. 2017. The role of the Hes1 crosstalk hub in Notch-Wnt interactions of the intestinal crypt. PLoS Computational Biology 13(2), article number: e1005400. (10.1371/journal.pcbi.1005400)
2016
- Clarke, P. A. et al. 2016. Assessing the mechanism and therapeutic potential of modulators of the human Mediator complex-associated protein kinases. eLife 5, article number: e20722. (10.7554/eLife.20722)
- Jardé, T. et al. 2016. Wnt and Neuregulin1/ErbB signalling extends 3D culture of hormone responsive mammary organoids. Nature Communications 7, article number: 13207. (10.1038/ncomms13207)
- Czodrowski, P. et al. 2016. Structure-based optimization of potent, selective, and orally bioavailable CDK8 inhibitors discovered by high-throughput screening. Journal of Medicinal Chemistry 59(20), pp. 9337-9349. (10.1021/acs.jmedchem.6b00597)
- Mallinger, A. et al. 2016. Discovery of potent, selective, and orally bioavailable small-molecule modulators of the mediator complex-associated kinases CDK8 and CDK19. Journal of Medicinal Chemistry 59(3), pp. 1078-1101. (10.1021/acs.jmedchem.5b01685)
2015
- Dale, T. et al. 2015. A selective chemical probe for exploring the role of CDK8 and CDK19 in human disease. Nature Chemical Biology 11, pp. 973-980. (10.1038/nchembio.1952)
- Freeman, J. et al. 2015. A functional connectome: regulation of Wnt/TCF-dependent transcription by pairs of pathway activators. Molecular Cancer 14, article number: 206. (10.1186/s12943-015-0475-1)
- Rada, P. et al. 2015. WNT-3A regulates an Axin1/NRF2 complex that regulates antioxidant metabolism in hepatocytes. Antioxidants & Redox Signaling 22(7), pp. 555-571. (10.1089/ars.2014.6040)
- Mallinger, A. et al. 2015. Discovery of potent, orally bioavailable, small-molecule inhibitors of WNT signaling from a cell-based pathway screen. Journal of Medicinal Chemistry 58(4), pp. 1717-1735. (10.1021/jm501436m)
2014
- Carotenuto, M. et al. 2014. H-Prune through GSK-3β interaction sustains canonical WNT/β-catenin signaling enhancing cancer progression in NSCLC. Oncotarget 5(14), pp. 5736-5749. (10.18632/oncotarget.2169)
- Rudge, F. and Dale, T. C. 2014. Therapeutic targeting of the Wnt signaling network. In: Hoppler, S. P. and Moon, R. T. eds. Wnt Signaling in Development and Disease: Molecular Mechanisms and Biological Functions. John Wiley & Sons, pp. 421-443.
- de Groot, R. E. A. et al. 2014. Huwe1-mediated ubiquitylation of dishevelled defines a negative feedback loop in the Wnt signaling pathway. Science Signaling 7(317), article number: ra26. (10.1126/scisignal.2004985)
2013
- Jarde, T. et al. 2013. In vivo and in vitro models for the therapeutic targeting of Wnt signaling using a Tet-OΔN89β-catenin system. Oncogene 32(7), pp. 883-893. (10.1038/onc.2012.103)
- Lloyd-Lewis, B., Fletcher, A. G., Dale, T. C. and Byrne, H. M. 2013. Toward a quantitative understanding of the Wnt/β-catenin pathway through simulation and experiment. Wiley Interdisciplinary Reviews: Systems Biology and Medicine 5(4), pp. 391-407. (10.1002/wsbm.1221)
2012
- Feng, G. J. et al. 2012. Conditional disruption of Axin1 leads to development of liver tumors in mice. Gastroenterology 143(6), pp. 1650-1659. (10.1053/j.gastro.2012.08.047)
- Shorning, B. et al. 2012. Intestinal renin-angiotensin system is stimulated after deletion of Lkb1. Gut 61(2), pp. 202-213. (10.1136/gutjnl-2011-300046)
- Jarde, T. and Dale, T. C. 2012. Wnt signalling in murine postnatal mammary gland development. Acta Physiologica 204(1), pp. 118-127. (10.1111/j.1748-1716.2011.02283.x)
- Braun, S., Humphreys, C. and Dale, T. C. 2012. Evolutionary routes from a prebiotic ANA-world. Communicative & Integrative Biology 5(2), pp. 199-202. (10.4161/cib.18892)
2011
- Braun, S., Humphreys, C., Fraser, E., Brancale, A., Bochtler, M. and Dale, T. C. 2011. Amyloid-Associated Nucleic Acid Hybridisation. PLoS ONE 6(5), article number: e19125. (10.1371/journal.pone.0019125)
- Perrins, R. D. et al. 2011. Doing more with less: a method for low total mass, affinity measurement using variable-length nanotethers. Analytical Chemistry 83(23), pp. 8900-8905. (10.1021/ac2012569)
2010
- Ewan, K. B. R. et al. 2010. A useful approach to identify novel small-molecule inhibitors of Wnt-dependent transcription. Cancer Research 70(14), pp. 5963-5973. (10.1158/0008-5472.CAN-10-1028)
- Wolkenhauer, O. et al. 2010. Systems biologists seek fuller integration of systems biology approaches in new cancer research programs. Cancer Research 70(1), pp. 12-13. (10.1158/0008-5472.CAN-09-2676)
2009
- Kasry, A., Borri, P., Davies, P. R., Harwood, A. J., Thomas, N., Lofas, S. and Dale, T. C. 2009. Comparison of methods for generating planar DNA-modified surfaces for hybridization studies. ACS Applied Materials & Interfaces 1(8), pp. 1793-1798. (10.1021/am9003073)
2008
- Kadri, H., Dale, T. C., Ewan, K. B. R. and Westwell, A. 2008. The design, synthesis and antitumour evaluation of novel small molecule inhibitors of the Dishevelled PDZ domain [Poster Presentation/Abstract]. EJC Supplements 6(12), pp. 137., article number: 436. (10.1016/S1359-6349(08)72370-X)
- Freeman, J., Zollo, M. and Dale, T. C. 2008. Investigating h-Prune activation of Wnt signalling in breast cancer. Breast Cancer Research 10(s2), pp. 10. (10.1186/bcr1899)
- Phesse, T., Parry, L., Reed, K. R., Ewan, K. B. R., Dale, T. C., Sansom, O. J. and Clarke, A. R. 2008. Deficiency of Mbd2 attenuates Wnt induced tumourigenesis via deregulation of a novel Wnt inhibitor, Lect.2. Molecular and Cellular Biology 28(19), pp. 6094-6103. (10.1128/MCB.00539-08)
- Ewan, K. B. R. and Dale, T. C. 2008. The potential for targeting oncogenic WNT/beta-catenin signaling in therapy. Current Drug Targets 9(7), pp. 532-547. (10.2174/138945008784911787)
- Dale, T. C., Harwood, A. J. and Borri, P. 2008. Method of measuring the affinity of biomolecules. EP1949104A2 [Patent].
2007
- Oosterveen, T., Coudreuse, D. Y., Yang, P., Fraser, E., Bergsma, J., Dale, T. C. and Korswagen, H. C. 2007. Two functionally distinct Axin-like proteins regulate canonical Wnt signaling in C. elegans. Developmental Biology 308(2), pp. 438-448. (10.1016/j.ydbio.2007.05.043)
- Forde, J. and Dale, T. C. 2007. Glycogen synthase kinase 3: A key regulator of cellular fate. Cellular and Molecular Life Sciences 64(15), pp. 1930-1944. (10.1007/s00018-007-7045-7)
2006
- Dale, T. C. 2006. Protein and nucleic acid together: A mechanism for the emergence of biological selection. Journal of Theoretical Biology 240(3), pp. 337-342. (10.1016/j.jtbi.2005.09.027)
- Dale, T. C. 2006. Kinase cogs go forward and reverse in the Wnt signaling machine. Nature Structural & Molecular Biology 13(1), pp. 9-11. (10.1038/nsmb0106-9)
2005
- Dale, T. C., Jonker, J., Mesman, E. and Schinkel, A. 2005. The Breast Cancer Resistance Protein (BCRP/ABCG2) concentrates drugs and carcinogenic xenotoxins into milk. Nature Medicine volume(issue), pp. 127-129. (10.1038/nm1186)
- Le Floch, N., Rivat, C., De Wever, O., Bruyneel, E., Mareel, M., Dale, T. C. and Gespach, C. 2005. The proinvasive activity of Wnt-2 is mediated through a noncanonical Wnt pathway coupled to GSK-3 and c-Jun/AP-1 signaling. The FASEB Journal 19(1), pp. 144-146. (10.1096/fj.04-2373fje)
- Jonker, J. W. et al. 2005. Contribution of the ABC transporters Bcrp1 and Mdr1a/1b to the side population phenotype in mammary gland and bone marrow of mice. Stem Cells 23(8), pp. 1059-1065. (10.1634/stemcells.2005-0150)
- Smalley, M. J. et al. 2005. Dishevelled (Dvl-2) activates canonical Wnt signalling in the absence of cytoplasmic puncta. Journal of Cell Science 118(22), pp. 5279-5289. (10.1242/jcs.02647)
2004
- Roberts, M. S., Woods, A. J., Dale, T. C., van der Sluijs, P. and Norman, J. C. 2004. Protein kinase B/Akt acts via glycogen synthase kinase 3 to regulate recycling of αvβ3 and α5β1 integrins. Molecular and Cellular Biology 24(4), pp. 1505-1515. (10.1128/MCB.24.4.1505-1515.2004)
- Ciani, L., Krylova, O., Smalley, M. J., Dale, T. C. and Salinas, P. 2004. A divergent canonical WNT-signaling pathway regulates microtubule dynamics: Dishevelled signals locally to stabilize microtubules. Journal of Cell Biology 164(2), pp. 243-253. (10.1083/jcb.200309096)
2003
- Dajani, R. et al. 2003. Structural basis for recruitment of glycogen synthase kinase 3beta to the axin-APC scaffold complex. The EMBO Journal 22(3), pp. 494-501. (10.1093/emboj/cdg068)
- Alvi, A. J. et al. 2003. Functional and molecular characterisation of mammary side population cells. Breast Cancer Research 5(1), pp. R1-R8. (10.1186/bcr547)
2002
- Franca-Koh, J., Yeo, M., Fraser, E., Young, N. and Dale, T. C. 2002. The regulation of glycogen synthase kinase-3 nuclear export by Frat/GBP. Journal of Biological Chemistry, pp. 43844-43848. (10.1074/jbc.M207265200)
- Fraser, E. et al. 2002. Identification of the Axin and Frat binding region of glycogen synthase kinase-3. Journal of Biological Chemistry 277(3), pp. 2176-2185. (10.1074/jbc.M109462200)
- Ding, Y. and Dale, T. C. 2002. Wnt signal transduction: kinase cogs in a nano-machine?. Trends in Biochemical Sciences 27(7), pp. 327-329. (10.1016/S0968-0004(02)02137-0)
2001
- Dajani, R., Fraser, E., Roe, S. M., Young, N., Good, V., Dale, T. C. and Pearl, L. H. 2001. Crystal structure of glycogen synthase kinase 3β : structural basis for phosphate-primed substrate specificity and autoinhibition. Cell 105(6), pp. 721-732. (10.1016/S0092-8674(01)00374-9)
- Smalley, M. J. and Dale, T. C. 2001. Wnt signaling and mammary tumorigenesis. Journal of Mammary Gland Biology and Neoplasia 6(1), pp. 37-52.
- Heisenberg, C. -. et al. 2001. A mutation in the Gsk3-binding domain of zebrafish Masterblind/Axin1 leads to a fate transformation of telencephalon and eyes to diencephalon. Genes & Development 15(11), pp. 1427-1434. (10.1101/gad.194301)
2000
- Sarkar, L., Cobourne, M., Naylor, S., Smalley, M. J., Dale, T. C. and Sharpe, P. T. 2000. Wnt/Shh interactions regulate ectodermal boundary formation during mammalian tooth development. Proceedings of the National Academy of Sciences of the United States of America 97(9), pp. 4520-4524. (10.1073/pnas.97.9.4520)
- Webster, M. T. et al. 2000. Sequence variants of the Axin gene in breast, colon, and other cancers: an analysis of mutations that interfere with GSK3 binding. Genes Chromosomes and Cancer 28(4), pp. 443-453. (10.1002/1098-2264(200008)28:4<443::AID-GCC10>3.0.CO;2-D)
- Naylor, S., Smalley, M. J., Robertson, D., Gusterson, B. A., Edwards, P. A. and Dale, T. C. 2000. Retroviral expression of Wnt-1 and Wnt-7b produces different effects in mouse mammary epithelium. Journal of Cell Science 113(12), pp. 2129-2138.
1999
- Smalley, M. J. and Dale, T. C. 1999. Wnt signalling in mammalian development and cancer. Cancer and Metastasis Reviews 18(2), pp. 215-230. (10.1023/A:1006369223282)
Articles
- Moore, J. W., Dale, T. C. and Woolley, T. E. 2023. Modelling polarity-driven laminar patterns in bilayer tissues with mixed signalling mechanisms. SIAM Journal on Applied Dynamical Systems 22(4), pp. 2945-2990. (10.1137/22M1522565)
- Moore, J. W., Dale, T. C. and Woolley, T. E. 2022. Polarity driven laminar pattern formation by lateral-inhibition in 2D and 3D bilayer geometries. IMA Journal of Applied Mathematics 87(4), pp. 568-606.
- Engel, R. M. et al. 2022. Modeling colorectal cancer: A bio-resource of 50 patient-derived organoid lines. Journal of Gastroenterology and Hepatology 37(5), pp. 898-907. (10.1111/jgh.15818)
- Moore, J. W., Lau, Z., Kaouri, K., Dale, T. C. and Woolley, T. E. 2021. A general computational framework for COVID-19 modelling with applications to testing varied interventions in education environments. COVID 1(4), pp. 674-703. (10.3390/covid1040055)
- Pope, I. et al. 2021. Identifying subpopulations in multicellular systems by quantitative chemical imaging using label-free hyperspectral CARS microscopy. Analyst 146(7), pp. 2277-2291. (10.1039/D0AN02381G)
- Badder, L. M. et al. 2020. 3D imaging of colorectal cancer organoids identifies responses to Tankyrase inhibitors. PLoS ONE 15(8), article number: e0235319. (10.1371/journal.pone.0235319)
- Valle-Encinas, E. and Dale, T. C. 2020. Wnt ligand and receptor patterning in the liver. Current Opinion in Cell Biology 62, pp. 17-25. (10.1016/j.ceb.2019.07.014)
- Young, R. M., Ewan, K. B., Ferrer, V. P., Allende, M. L., Godovac-Zimmermann, J., Dale, T. C. and Wilson, S. W. 2019. Developmentally regulated Tcf7l2 splice variants mediate transcriptional repressor functions during eye formation. eLife 8, article number: e51447. (10.7554/eLife.51447)
- Dietrich, L. et al. 2017. Cell permeable stapled peptide inhibitor of Wnt signaling that targets β-catenin protein‒protein interactions. Cell Chemical Biology 24(8), pp. 958-968., article number: e5. (10.1016/j.chembiol.2017.06.013)
- Carotenuto, P. et al. 2017. Wnt signalling modulates transcribed-ultraconserved regions in hepatobiliary cancers. Gut 66(7), pp. 1268-1277. (10.1136/gutjnl-2016-312278)
- Kay, S. K. et al. 2017. The role of the Hes1 crosstalk hub in Notch-Wnt interactions of the intestinal crypt. PLoS Computational Biology 13(2), article number: e1005400. (10.1371/journal.pcbi.1005400)
- Clarke, P. A. et al. 2016. Assessing the mechanism and therapeutic potential of modulators of the human Mediator complex-associated protein kinases. eLife 5, article number: e20722. (10.7554/eLife.20722)
- Jardé, T. et al. 2016. Wnt and Neuregulin1/ErbB signalling extends 3D culture of hormone responsive mammary organoids. Nature Communications 7, article number: 13207. (10.1038/ncomms13207)
- Czodrowski, P. et al. 2016. Structure-based optimization of potent, selective, and orally bioavailable CDK8 inhibitors discovered by high-throughput screening. Journal of Medicinal Chemistry 59(20), pp. 9337-9349. (10.1021/acs.jmedchem.6b00597)
- Mallinger, A. et al. 2016. Discovery of potent, selective, and orally bioavailable small-molecule modulators of the mediator complex-associated kinases CDK8 and CDK19. Journal of Medicinal Chemistry 59(3), pp. 1078-1101. (10.1021/acs.jmedchem.5b01685)
- Dale, T. et al. 2015. A selective chemical probe for exploring the role of CDK8 and CDK19 in human disease. Nature Chemical Biology 11, pp. 973-980. (10.1038/nchembio.1952)
- Freeman, J. et al. 2015. A functional connectome: regulation of Wnt/TCF-dependent transcription by pairs of pathway activators. Molecular Cancer 14, article number: 206. (10.1186/s12943-015-0475-1)
- Rada, P. et al. 2015. WNT-3A regulates an Axin1/NRF2 complex that regulates antioxidant metabolism in hepatocytes. Antioxidants & Redox Signaling 22(7), pp. 555-571. (10.1089/ars.2014.6040)
- Mallinger, A. et al. 2015. Discovery of potent, orally bioavailable, small-molecule inhibitors of WNT signaling from a cell-based pathway screen. Journal of Medicinal Chemistry 58(4), pp. 1717-1735. (10.1021/jm501436m)
- Carotenuto, M. et al. 2014. H-Prune through GSK-3β interaction sustains canonical WNT/β-catenin signaling enhancing cancer progression in NSCLC. Oncotarget 5(14), pp. 5736-5749. (10.18632/oncotarget.2169)
- de Groot, R. E. A. et al. 2014. Huwe1-mediated ubiquitylation of dishevelled defines a negative feedback loop in the Wnt signaling pathway. Science Signaling 7(317), article number: ra26. (10.1126/scisignal.2004985)
- Jarde, T. et al. 2013. In vivo and in vitro models for the therapeutic targeting of Wnt signaling using a Tet-OΔN89β-catenin system. Oncogene 32(7), pp. 883-893. (10.1038/onc.2012.103)
- Lloyd-Lewis, B., Fletcher, A. G., Dale, T. C. and Byrne, H. M. 2013. Toward a quantitative understanding of the Wnt/β-catenin pathway through simulation and experiment. Wiley Interdisciplinary Reviews: Systems Biology and Medicine 5(4), pp. 391-407. (10.1002/wsbm.1221)
- Feng, G. J. et al. 2012. Conditional disruption of Axin1 leads to development of liver tumors in mice. Gastroenterology 143(6), pp. 1650-1659. (10.1053/j.gastro.2012.08.047)
- Shorning, B. et al. 2012. Intestinal renin-angiotensin system is stimulated after deletion of Lkb1. Gut 61(2), pp. 202-213. (10.1136/gutjnl-2011-300046)
- Jarde, T. and Dale, T. C. 2012. Wnt signalling in murine postnatal mammary gland development. Acta Physiologica 204(1), pp. 118-127. (10.1111/j.1748-1716.2011.02283.x)
- Braun, S., Humphreys, C. and Dale, T. C. 2012. Evolutionary routes from a prebiotic ANA-world. Communicative & Integrative Biology 5(2), pp. 199-202. (10.4161/cib.18892)
- Braun, S., Humphreys, C., Fraser, E., Brancale, A., Bochtler, M. and Dale, T. C. 2011. Amyloid-Associated Nucleic Acid Hybridisation. PLoS ONE 6(5), article number: e19125. (10.1371/journal.pone.0019125)
- Perrins, R. D. et al. 2011. Doing more with less: a method for low total mass, affinity measurement using variable-length nanotethers. Analytical Chemistry 83(23), pp. 8900-8905. (10.1021/ac2012569)
- Ewan, K. B. R. et al. 2010. A useful approach to identify novel small-molecule inhibitors of Wnt-dependent transcription. Cancer Research 70(14), pp. 5963-5973. (10.1158/0008-5472.CAN-10-1028)
- Wolkenhauer, O. et al. 2010. Systems biologists seek fuller integration of systems biology approaches in new cancer research programs. Cancer Research 70(1), pp. 12-13. (10.1158/0008-5472.CAN-09-2676)
- Kasry, A., Borri, P., Davies, P. R., Harwood, A. J., Thomas, N., Lofas, S. and Dale, T. C. 2009. Comparison of methods for generating planar DNA-modified surfaces for hybridization studies. ACS Applied Materials & Interfaces 1(8), pp. 1793-1798. (10.1021/am9003073)
- Kadri, H., Dale, T. C., Ewan, K. B. R. and Westwell, A. 2008. The design, synthesis and antitumour evaluation of novel small molecule inhibitors of the Dishevelled PDZ domain [Poster Presentation/Abstract]. EJC Supplements 6(12), pp. 137., article number: 436. (10.1016/S1359-6349(08)72370-X)
- Freeman, J., Zollo, M. and Dale, T. C. 2008. Investigating h-Prune activation of Wnt signalling in breast cancer. Breast Cancer Research 10(s2), pp. 10. (10.1186/bcr1899)
- Phesse, T., Parry, L., Reed, K. R., Ewan, K. B. R., Dale, T. C., Sansom, O. J. and Clarke, A. R. 2008. Deficiency of Mbd2 attenuates Wnt induced tumourigenesis via deregulation of a novel Wnt inhibitor, Lect.2. Molecular and Cellular Biology 28(19), pp. 6094-6103. (10.1128/MCB.00539-08)
- Ewan, K. B. R. and Dale, T. C. 2008. The potential for targeting oncogenic WNT/beta-catenin signaling in therapy. Current Drug Targets 9(7), pp. 532-547. (10.2174/138945008784911787)
- Oosterveen, T., Coudreuse, D. Y., Yang, P., Fraser, E., Bergsma, J., Dale, T. C. and Korswagen, H. C. 2007. Two functionally distinct Axin-like proteins regulate canonical Wnt signaling in C. elegans. Developmental Biology 308(2), pp. 438-448. (10.1016/j.ydbio.2007.05.043)
- Forde, J. and Dale, T. C. 2007. Glycogen synthase kinase 3: A key regulator of cellular fate. Cellular and Molecular Life Sciences 64(15), pp. 1930-1944. (10.1007/s00018-007-7045-7)
- Dale, T. C. 2006. Protein and nucleic acid together: A mechanism for the emergence of biological selection. Journal of Theoretical Biology 240(3), pp. 337-342. (10.1016/j.jtbi.2005.09.027)
- Dale, T. C. 2006. Kinase cogs go forward and reverse in the Wnt signaling machine. Nature Structural & Molecular Biology 13(1), pp. 9-11. (10.1038/nsmb0106-9)
- Dale, T. C., Jonker, J., Mesman, E. and Schinkel, A. 2005. The Breast Cancer Resistance Protein (BCRP/ABCG2) concentrates drugs and carcinogenic xenotoxins into milk. Nature Medicine volume(issue), pp. 127-129. (10.1038/nm1186)
- Le Floch, N., Rivat, C., De Wever, O., Bruyneel, E., Mareel, M., Dale, T. C. and Gespach, C. 2005. The proinvasive activity of Wnt-2 is mediated through a noncanonical Wnt pathway coupled to GSK-3 and c-Jun/AP-1 signaling. The FASEB Journal 19(1), pp. 144-146. (10.1096/fj.04-2373fje)
- Jonker, J. W. et al. 2005. Contribution of the ABC transporters Bcrp1 and Mdr1a/1b to the side population phenotype in mammary gland and bone marrow of mice. Stem Cells 23(8), pp. 1059-1065. (10.1634/stemcells.2005-0150)
- Smalley, M. J. et al. 2005. Dishevelled (Dvl-2) activates canonical Wnt signalling in the absence of cytoplasmic puncta. Journal of Cell Science 118(22), pp. 5279-5289. (10.1242/jcs.02647)
- Roberts, M. S., Woods, A. J., Dale, T. C., van der Sluijs, P. and Norman, J. C. 2004. Protein kinase B/Akt acts via glycogen synthase kinase 3 to regulate recycling of αvβ3 and α5β1 integrins. Molecular and Cellular Biology 24(4), pp. 1505-1515. (10.1128/MCB.24.4.1505-1515.2004)
- Ciani, L., Krylova, O., Smalley, M. J., Dale, T. C. and Salinas, P. 2004. A divergent canonical WNT-signaling pathway regulates microtubule dynamics: Dishevelled signals locally to stabilize microtubules. Journal of Cell Biology 164(2), pp. 243-253. (10.1083/jcb.200309096)
- Dajani, R. et al. 2003. Structural basis for recruitment of glycogen synthase kinase 3beta to the axin-APC scaffold complex. The EMBO Journal 22(3), pp. 494-501. (10.1093/emboj/cdg068)
- Alvi, A. J. et al. 2003. Functional and molecular characterisation of mammary side population cells. Breast Cancer Research 5(1), pp. R1-R8. (10.1186/bcr547)
- Franca-Koh, J., Yeo, M., Fraser, E., Young, N. and Dale, T. C. 2002. The regulation of glycogen synthase kinase-3 nuclear export by Frat/GBP. Journal of Biological Chemistry, pp. 43844-43848. (10.1074/jbc.M207265200)
- Fraser, E. et al. 2002. Identification of the Axin and Frat binding region of glycogen synthase kinase-3. Journal of Biological Chemistry 277(3), pp. 2176-2185. (10.1074/jbc.M109462200)
- Ding, Y. and Dale, T. C. 2002. Wnt signal transduction: kinase cogs in a nano-machine?. Trends in Biochemical Sciences 27(7), pp. 327-329. (10.1016/S0968-0004(02)02137-0)
- Dajani, R., Fraser, E., Roe, S. M., Young, N., Good, V., Dale, T. C. and Pearl, L. H. 2001. Crystal structure of glycogen synthase kinase 3β : structural basis for phosphate-primed substrate specificity and autoinhibition. Cell 105(6), pp. 721-732. (10.1016/S0092-8674(01)00374-9)
- Smalley, M. J. and Dale, T. C. 2001. Wnt signaling and mammary tumorigenesis. Journal of Mammary Gland Biology and Neoplasia 6(1), pp. 37-52.
- Heisenberg, C. -. et al. 2001. A mutation in the Gsk3-binding domain of zebrafish Masterblind/Axin1 leads to a fate transformation of telencephalon and eyes to diencephalon. Genes & Development 15(11), pp. 1427-1434. (10.1101/gad.194301)
- Sarkar, L., Cobourne, M., Naylor, S., Smalley, M. J., Dale, T. C. and Sharpe, P. T. 2000. Wnt/Shh interactions regulate ectodermal boundary formation during mammalian tooth development. Proceedings of the National Academy of Sciences of the United States of America 97(9), pp. 4520-4524. (10.1073/pnas.97.9.4520)
- Webster, M. T. et al. 2000. Sequence variants of the Axin gene in breast, colon, and other cancers: an analysis of mutations that interfere with GSK3 binding. Genes Chromosomes and Cancer 28(4), pp. 443-453. (10.1002/1098-2264(200008)28:4<443::AID-GCC10>3.0.CO;2-D)
- Naylor, S., Smalley, M. J., Robertson, D., Gusterson, B. A., Edwards, P. A. and Dale, T. C. 2000. Retroviral expression of Wnt-1 and Wnt-7b produces different effects in mouse mammary epithelium. Journal of Cell Science 113(12), pp. 2129-2138.
- Smalley, M. J. and Dale, T. C. 1999. Wnt signalling in mammalian development and cancer. Cancer and Metastasis Reviews 18(2), pp. 215-230. (10.1023/A:1006369223282)
Book sections
- Rudge, F. and Dale, T. C. 2014. Therapeutic targeting of the Wnt signaling network. In: Hoppler, S. P. and Moon, R. T. eds. Wnt Signaling in Development and Disease: Molecular Mechanisms and Biological Functions. John Wiley & Sons, pp. 421-443.
Conferences
- Pope, I. et al. 2018. Coherent Raman Scattering microscopy: technology developments and biological applications. Presented at: 20th International Conference on Transparent Optical Networks (ICTON), Bucharest, Romania, 1-5 Jul 201820th International Conference on Transparent Optical Networks (ICTON). IEEE, (10.1109/ICTON.2018.8473706)
Patents
- Dale, T. C., Harwood, A. J. and Borri, P. 2008. Method of measuring the affinity of biomolecules. EP1949104A2 [Patent].
Ymchwil
Sgrinio ar gyfer genynnau a moleciwlau bach sy'n modiwleiddio signalau Wnt / β-catenin
Mae'r llwybr Wnt/β-catenin yn cael ei actifadu mewn ystod eang o diwmorau. Mae sgrinio celloedd yn ffordd effeithlon o adnabod rheolyddion Wnt / β-catenin nofel. Rydym wedi defnyddio sgrinio celloedd trwybwn uchel i nodi proteinau newydd a moleciwlau bach sy'n rheoleiddio'r llwybr. Mae'r proteinau nofel a'r moleciwlau bach yn cael eu defnyddio i ddechrau fel offer moleciwlaidd i nodweddu llwybr Wnt ymhellach. Mae hyn wedi ein galluogi i ddangos bod llwybr Wnt yn ymddwyn fel rhwydwaith moleciwlaidd. Mae rhai o'r moleciwlau bach bellach yn cael eu datblygu fel therapiwteg ymgeiswyr ar gyfer canser colorectal a chanser y fron mewn cydweithrediad mawr â Merck Serono.
Ffigur 1: Sgrinio ar gyfer modulatyddion llwybr Wnt
A: Strategaeth Sgrinio. Mae colli swyddogaeth (siRNA) ac ennill sgriniau graddfa genom swyddogaeth (cDNA) wedi'u cynnal mewn llinellau celloedd adroddwr gan ddefnyddio gweithgaredd gohebydd dibynnol TCF a digonedd / lleoliad b-catenin fel darlleniadau. Sgriniwyd llyfrgelloedd cemegol ar gyfer atalyddion moleciwlau bach signalau Wnt / β-catenin. Arweiniodd hyn at brosiect darganfod cyffuriau ar raddfa fawr mewn cydweithrediad â Merck-Serono, y Sefydliad Ymchwil Canser a Thechnoleg Ymchwil Canser.
B: Mae'r llinell gohebydd TCF 7dF3 . Mae'r celloedd sy'n seiliedig ar HEK293 yn cynnwys gohebydd TCF a rheoleiddiwr Wnt i fyny'r afon anorchfygol (protein ymasiad derbynnydd Dishevelled-oestrogen Dsh-ER). Yn y llinell gell hon, mae Estradiol (E2) yn actifadu trawsgrifiad dibynnol TCF ~ 12X. Mae'r atalydd GSK-3 Li + yn actifadu gweithgaredd adroddwr TCF 11,000X. (Ailgyfeiriad oddi wrth Ewan et al. 2010)
Diwylliant Organoid
Mae systemau diwylliant cynradd tri dimensiwn yn fwy perthnasol ar gyfer rhagweld cyfleustodau asiantau therapiwtig posibl i'w defnyddio mewn vivo na diwylliant 2D o linellau celloedd sefydledig. Mae datblygu systemau diwylliant organoid trwybwn canolig i brofi atalyddion llwybr Wnt yn gyfeiriad ymchwil pwysig i'r labordy. Mae diwylliant organoidau meinwe arferol a thiwmor yn cael eu datblygu.
Ffigur 2: Datblygu system diwylliant organoid berfeddol bach
A: Cynnal a chadw'r epitheliwm coluddyn bach gan y gilfach bôn-gelloedd. Dim ond wythnos yn y coluddyn bach y mae celloedd gwahaniaethol yn byw, felly mae strwythurau o'r enw crypts sy'n cynnwys celloedd coesyn a phroliferative yn ailgyflenwi'r coluddyn â chelloedd newydd yn barhaus. Mae'r celloedd hyn yn mudo o'r gilfach bôn-gelloedd, trwy barth amlochrog y crypt ac yn gwahaniaethu i gelloedd aeddfed wrth fynd i mewn i'r filws. Mae graddiant signalau Wnt / β-catenin, uchaf yn y gilfach bôn-gelloedd, yn rheoleiddio amlhau celloedd a gwahaniaethu.
B: Tet-O-ΔN89-β-catenin llinell llygoden. Gwnaethom ddatblygu llinell llygoden i fynegi β-catenin oncogenic (ΔN89-β-catenin) ym mhob math o gell yn amodol ar gyfer actifadu llwybr Wnt / β-catenin byd-eang. Mae mynegiant o ΔN89-β-catenin yn cael ei ysgogi gan Doxycycline, sy'n gweithredu fel 'switsh moleciwlaidd'. Mae hyn yn cymell hyperplasia y strwythurau crypt yn y coluddyn bach oherwydd bloc o wahaniaethu cellog.
C: diwylliant crypt berfeddol: Organoid wedi'i staenio ar gyfer gohebydd signalau Wnt (Axin2-lacZ). Mae'r organoid yn cynnwys epitheliwm o amgylch ceudod canolog. Mae'r alldafliadau lliw glas yn cyfateb i'r cryptiau ac mae epitheliwm heb ei gynnal y corff canolog yn cyfateb i'r filws. (Ailgyfeiriad oddi wrth Jarde et al., 2013)
Organoidau Colon Dynol
Delweddwyd twf organoidau sengl dros 4 diwrnod a gellir cyrchu'r fideos trwy'r dolenni hyn: organoid colon arferol , organoid tiwmor y colon .
Mae cymhwysiad masnachol o dechnoleg organoid yn cael ei archwilio gyda'r cwmni Cellesce (www.cellesce.com). Cwmni Spin Out yw hwn sy'n seiliedig ar waith o'r labordy hwn a gwaith Dr. Marianne Ellis ym Mhrifysgol Caerfaddon.
Rôl Axin1 yn natblygiad tiwmorau'r afu
Mae mwtaniadau mewn genynnau sy'n amgodio proteinau yn llwybr signalau Wnt, gan gynnwys CTNNB1 (β-catenin genyn) a'r AXIN1 protein rhwymo GSK-3, i'w cael mewn mwy na 50% o garcinomas hepatogellol dynol (HCC). Datblygwyd model murin i amharu ar swyddogaeth y genynnau Axin1 ac Axin2 yn yr afu. Dangosodd afu nad oedd Axin1 fwy o amlhau celloedd a datblygu tiwmorau'r afu a oedd yn cyd-fynd â'r isfath o ganser yr afu dynol lle mae treigladau Axin i'w cael. Yn rhyfeddol, mae'r newidiadau a welwyd yn dilyn colled Axin yn wahanol i'r rhai sy'n nodweddiadol o weithrediad llwybr Wnt sy'n awgrymu y gallai Axin repress canser yr afu trwy lwybr moleciwlaidd newydd.
Ffigur 3: Tiwmorau mewn dau iau llygoden sy'n ddiffygiol yn swyddogaeth genynnau Axin1. Amharwyd ar Axin1 yn yr afu flwyddyn cyn ei dorri. Nodir ffiniau'r tiwmor gyda llinellau gwyn wedi'u chwalu. (Ailgyfeiriad oddi wrth Feng et al. 2013)
Biocemeg a Strwythur Cydrannau Llwybr Signalau Wnt / β-catenin
Mae gennym ddiddordeb arbennig mewn astudio sut mae trosiant β-catenin yn cael ei newid yn dilyn ligand Wnt rhwymo ar wyneb y gell a dilyn mwtaniadau oncogenig. Mae ligands Wnt a newidiadau oncogenig yn sefydlogi β-catenin ac yn actifadu trawsgrifiad dibynnol β-catenin/TCF. Nod y gwaith yw deall sut mae'r newidiadau hyn yn newid cyfansoddiad a rhyngweithiadau rhwng cydrannau cymhleth trosiant β-catenin megis APC, Axin a CK1.
Ffigur 4: Biocemeg llwybr signalau Wnt.
A: Llwybr: Yn absenoldeb signal Wnt, mae'r cyfadeilad trosiant β-catenin yn gwella diraddio β-catenin. Ym mhresenoldeb ligands Wnt, mae swyddogaeth y β-catenin trosiant cymhleth yn cael ei rwystro gan arwain at grynhoi β-catenin, sydd wedyn yn trosglwyddo i'r cnewyllyn ac yn gweithredu fel ffactor cyd-drawsgrifio gydag aelodau o deulu protein rhwymo DNA TCF. Dangoswyd bod treigladau i aelodau teulu Wnt, Axin, APC, β-catenin a TCF yn cymell tiwmorau ac yn actifadu trawsgrifiad dibynnol ar TCF. Mae dros gant o reoleiddwyr ychwanegol nad ydynt yn cael eu dangos yn y diagram llinellol hwn yn cynnwys rhwydwaith signalau Wnt.
B: rhyngweithio GSK-3 / Axin: Mae gwaith ar y cyd â Laurence Pearl (Prifysgol Surrey) yn canolbwyntio ar y kinase GSK-3 sy'n chwarae rhan ganolog wrth dargedu β-catenin ar gyfer diraddio o fewn y safle trosiant β-catenin. Rydym yn penderfynu strwythur GSK-3 a chymhlethdod rhwng GSK-3 ac Axin. Mae'r astudiaethau hyn wedi darparu mewnwelediadau pwysig i'r mecanweithiau sy'n sail i gydnabyddiaeth a rheoleiddio swbstrad GSK-3. (Ailgyfeiriad oddi wrth Dajani et al., 2003)
Sgrinio trwybwn uchel ar gyfer rhyngweithio protein
Y cam arafaf mewn llawer o brofion biocemegol yw cynhyrchu a phuro digon o brotein ar gyfer profion meintiol. Mewn cydweithrediad â'r Athro Adrian Harwood a Paola Borri, rydym wedi datblygu techneg newydd o'r enw 'Nanotether' a allai dorri'r dagfa biocemegol hon.
Y syniad y tu ôl i'r dechnoleg yw tennyn dau biofolecwl i ben tetherau hyblyg (DNA) fel y gallant ryngweithio mewn cyfaint ar raddfa nano. Mae smotiau wedi'u haddurno o foleciwlau sy'n rhyngweithio sy'n cynnwys cyn lleied ag 1 miliwn o foleciwlau yn cael eu dadansoddi gan FRET i fesur cyfran y biomolecwlau tethered.
Prif fanteision technoleg yw:
- Mae araeau tethered o barau moleciwl yn cael eu cydosod yn hawdd gan hybrid DNA.
- Mae croesiad yn canolbwyntio'r moleciwlau rhyngweithio ger yr wyneb tra bod hyd y tetherau yn rheoli'r crynodiad effeithiol (ystod nM-uM isel).
- Gellir cynhyrchu crynodiadau uchel (> 10uM) o fàs isel o brotein - dylai hyn fod yn gydnaws â thechnegau fel cyfieithu in vitro.
Mae'r dechnoleg hon bellach yn cael ei datblygu'n fasnachol mewn cwmni deillio o Brifysgol Caerdydd. Bydd yr ardal ymgeisio gyntaf yn brofion rhwymo protein kinase trwybwn uchel. Gweler www.nanotether.co.uk (Gellir dod o hyd i dystiolaeth o ddata cysyniad yn Perrins et al. 2011.)
Signalau Wnt / β-catenin a Datblygu Mammari a Tumourigenesis
Mae'r chwarren mammari yn cael nifer o brosesau datblygu ar ôl natnatally, o ymestyn y strwythur tebyg i goeden ductal i ddatblygiad beichiogrwydd yr unedau lobulo-alfeolar sy'n gwneud llaeth. Awgrymwyd bod bôn-gelloedd epithelaidd mammari yn ganolog i reoli ehangu ac ailfodelu meinwe enfawr yn ystod y cyfnodau hyn o ddatblygiad mammari. Mae llwybr signalau Wnt yn chwarae rhan hanfodol yn y camau biolegol hyn ac awgrymir ei fod yn ymwneud â chynnal a chadw'r boblogaeth bôn-gelloedd. Mae hefyd wedi cael ei gysylltu mewn rhai mathau o ganser y fron.
Ffigur 6: Signalau Wnt mewn datblygiad arferol a chanser.
A: Mae Wnts yn rheoleiddio datblygiad arferol. Yn y chwarren fammari, mae rhai aelodau teulu Wnt yn ymwneud â rheoli datblygiad lobular.
B: Wnt ligand fel mammary oncogene. Yn wreiddiol, nodwyd aelod prototeip y teulu Wnt (Wnt-1) fel oncogene mammari ac mae'n achosi newidiadau cyn-ganseraidd dramatig yn epitheliwm mammari.
Addysgu
Teaching includes:
Module Lead for Masters Module 'Frontiers in Bioscience' BI4003
MRes Bioscience 'Research Techniques in Bioscience' BIT002
Cancer: Cellular and Molecular Mechanisms and Therapeutics BI3352
Synthetic Biology and Protein Engineering BI3255
Bywgraffiad
Fe wnes i fy ngradd israddedig mewn Biocemeg yng Ngholeg Imperial ac yna cwblheais PhD ar drawsosod signal ymyrryd yn y Gronfa Ymchwil Canser Imperial ym 1989 (bellach Cancer Research UK, London Research Centre). Yn ystod y cyfnod hwn, daeth gen i ddiddordeb yn rôl llwybrau signalau mewn datblygiad. Yn dilyn cymrodoriaeth ôl-ddoethurol yng Ngholeg Meddygaeth Baylor yn Houston, sefydlais grŵp ymchwil yn y Sefydliad Ymchwil Canser yn Llundain ym 1991.
Symudodd fy ngrŵp i Gaerdydd ym mis Tachwedd 2003.
Themâu ymchwil
Arbenigeddau
- Biocemeg a bioleg celloedd
- Geneteg ddatblygiadol
- Bioleg synthetig
