Dr Colin Miles
- Email: email@example.com
- Telephone: +44 (0) 191 241 8699
- Fax: +44 (0) 191 241 8666
- Address: Institute of Genetic Medicine
International Centre for Life
Newcastle upon Tyne
The Wilms’ Tumour 1 Gene in Development and Disease.
Mutations in the Wilms’ tumour suppressor gene, WT1, cause kidney disease, childhood kidney cancer and leukaemia. In addition, WT1 is crucial for many other aspects of normal mammalian development and serves as a paradigm for aberrant development leading to human disease. To date, however, few bona fide target genes have been identified and the molecular pathways in which WT1 acts in normal development and disease remain poorly characterised. Research in my laboratory employs transgenic/gene targeting technology coupled with genomics/proteomics approaches to study the regulation and function of the WT1 gene during development in order to dissect the molecular and cellular mechanisms underlying these processes.
Glomerulosclerosis is a key and common feature of chronic kidney disease (over 140,000 affected in UK). WT1 mutation causes diffuse glomerulosclerosis in a rare condition known as Denys Drash Syndrome (DDS). We are identifying the initiating molecular and cellular events leading to glomerulosclerosis in a DDS model and building a molecular profile of disease progression in this model with a view to identifying novel diagnostic markers/potential therapeutic targets that may be relevant to the progression of glomerulosclerosis in general.
Expression of WT1 is a hallmark of the majority of all leukaemias. Consequently, WT1 is an attractive target for pan-leukaemic therapies. Although WT1 is readily detected in leukaemic cells, it has proven difficult to identify WT1 expressing cells in normal, healthy, bone marrow and therefore the normal physiological role of WT1 expressing cells and the function of WT1 remain unknown. If anti-WT1 strategies are to provide effective therapies, without adverse side-effects, it is essential to understand the role of WT1 and WT1 expressing cells in normal haematopoiesis. We are developing novel approaches to characterise WT1 expressing haematopoietic cells and dissect the role of WT1 within these cells.
In addition, the frequency of WT1 mutation in acute myeloid leukaemia (AML) is similar to that in Wilms’ tumour, implying that mutation of WT1 is a leukaemogenic event. We are creating and analysing models designed to mimic the situation in leukaemia to determine the role of WT1 mutation in leukaemia and the function of WT1 in normal haematopoiesis.
John Sayer - Academic Senior Lecturer
Ann Marie Hynes - PhD student
Parisa Javadian Elyaderani - PhD student
Kevin Gillinder - PhD student
- Florio F, Cesaro E, Montano G, Izzo P, Miles C, Costanzo P. Biochemical and functional interaction between ZNF224 and ZNF255, two members of the Krüppel-like zinc-finger protein family and WT1 protein isoforms. Human Molecular Genetics 2010, 19(18), 3544-3556.
- Patek CE, Brownstein DG, Fleming S, Wroe C, Rose L, Webb A, Berry RL, Devenney PS, Walker M, Maddocks ODK, Lawrence NJ, Harrison DJ, Wood KM, Miles CG, Hooper ML. Effects on kidney disease, fertility and development in mice inheriting a protein-truncating Denys-Drash syndrome allele (Wt1 tmT396). Transgenic Research 2008, 17(3), 459-475.
- Ruiz-Perez VL, Blair HJ, Rodrigues-Andres ME, Blanco MJ, Wilson A, Liu Y-N, Miles C, Peters H, Goodship JA. Evc is a positive mediator of Ihh-regulated bone growth that localises at the base of chondrocyte cilia. Development 2007, 134(16), 2903-2912.
- Werner A, Schmutzler G, Carlile M, Miles CG, Peters H. Expression profiling of antisense transcripts on DNA arrays. Physiological Genomics 2007, 28(3), 294-300.
- Spraggon L, Dudnakova T, Slight J, Lustig-Yariv O, Cotterell J, Hastie N, Miles C. hnRNP-U directly interacts with WT1 and modulates WT1 transcriptional activation. Oncogene 2007, 26(10), 1484-1491.
- Ijpenberg A, Pérez-Pomares JM, Guadix JA, Carmonab R, Portillo-Sánchez V, Macías D, Hohenstein P, Miles C, Hastie ND, Muñoz-Chápuli R. Wt1 and retinoic acid signaling are essential for stellate cell development and liver morphogenesis. Developmental Biology 2007, 312(1), 157-70.
- Patek CE, Saunders PTK, Miles CG, Berry RL, Hastie ND, Sharpe RM, Hooper ML. Gonadal effects of a mouse Denys-Drash Syndrome mutation. Transgenic Research 2005, 14(5), 691-702.
- Kist R, Watson M, Wang X, Cairns P, Miles C, Reid DJ, Peters H. Reduction of Pax9 gene dosage in an allelic series of mouse mutants causes hypodontia and oligodontia. Human Molecular Genetics 2005, 14(23), 3605-3617.
- Orelio C, Harvey KN, Miles C, Oostendorp RAJ, van der Horn K, Dzierzak E. The role of apoptosis in the development of AGM hematopoietic stem cells revealed by Bcl-2 overexpression. Blood 2004, 103(11), 4084-4092.
- Miles CG, Rankin L, Smith SI, Niksic M, Elgar G, Hastie ND. Faithful expression of a tagged Fugu WT1 protein from a genomic transgene in zebrafish: efficient splicing of pufferfish genes in zebrafish but not mice. Nucleic Acids Research 2003, 31(11), 2795-2802.
- James RM, Arends MJ, Plowman SJ, Brooks DG, Miles CG, West JD, Patek CE. K-ras proto-oncogene exhibits tumor suppressor activity as its absence promotes tumorigenesis in murine teratomas. Molecular Cancer Research 2003, 1(11), 820-825.
- Miles CG, Slight J, Spraggon L, O'Sullivan M, Patek C, Hastie ND. Mice Lacking the 68-Amino-Acid, Mammal-Specific N-Terminal Extension of WT1 Develop Normally and Are Fertile. Molecular and Cellular Biology 2003, 23(7), 2608-2613.
- Patek CE, Fleming S, Miles CG, Bellamy CO, Ladomery M, Spraggon L, Mullins J, Hastie ND, Hooper ML. Murine Denys-Drash syndrome: Evidence of podocyte de-differentiation and systemic mediation of glomerulosclerosis. Human Molecular Genetics 2003, 12(18), 2379-2394.
- Wagner KJ, Patek CE, Miles C, Christie S, Brookes AJ, Hooper ML. Truncation of WT1 results in downregulation of cyclin G1 and IGFBP-4 expression. Biochemical and Biophysical Research Communications 2001, 287(4), 977-982.
- Patek CE, Little MH, Fleming S, Miles C, Charlieu JP, Clarke AR, Miyagawa K, Christie S, Doig J, Harrison DJ, Porteous DJ, Brookes AJ, Hooper ML, Hastie ND. A zinc finger truncation of murine WT1 results in the characteristic urogenital abnormalities of Denys-Drash syndrome. Proceedings of the National Academy of Sciences of the United States of America 1999, 96(6), 2931-2936.
- Miles C, Elgar G, Coles E, Kleinjan DJ, van Heyningen V, Hastie N. Complete sequencing of the Fugu WAGR region from WT1 to PAX6: dramatic compaction and conservation of synteny with human chromosome 11p13. Proc Natl Acad Sci U S A 95:13068-72 1998.
- Miles C, Sanchez MJ, Sinclair A, Dzierzak E. Expression of the Ly-6E.1 (Sca-1) transgene in adult hematopoietic stem cells and the developing mouse embryo. Development 1997, 124(2), 537-47.
- Sánchez MJ, Holmes A, Miles C & Dzierzak E. Characterization of the First Definitive Hematopoietic Stem Cells in the AGM and Liver of the Mouse Embryo. Immunity 1996, 5(6), 513-525.
- Brady HJ, Abraham DJ, Pennington DJ, Miles CG, Jenkins S, Dzierzak EA. Altered cytokine expression in T lymphocytes from human immunodeficiency virus Tat transgenic mice. J.Virol 1995, 69(12), 7622-29.
- Brady HJ, Miles CG, Pennington DJ, Dzierzak EA. Specific ablation of human immunodeficiency virus Tat-expressing cells by conditionally toxic retroviruses. Proc Natl Acad Sci U S A 1994, 91(1), 365-69.
- Brady HJ, Pennington DJ, Miles CG, Dzierzak EA. CD4 cell surface downregulation in HIV-1 Nef transgenic mice is a consequence of intracellular sequestration. EMBO J 1993, 12(13), 4923-32.
- Brady HJ, Miles CG, Pennington DJ, Dzierzak EA. Studies of HIV-2 promoter activity and cell specific ablation. Leukemia 1993, 7(S2), S61-5.
- Srivastava S, Ramsbottom SA, Molinari E, Alkanderi S, Filby A, White K, Henry C, Saunier S, Miles CG, Sayer JA. A human patient-derived cellular model of Joubert syndrome reveals ciliary defects which can be rescued with targeted therapies. Human Molecular Genetics 2017, Epub ahead of print.
- Slaats GG, Saldivar JC, Bacal J, Zeman MK, Kile AC, Hynes AM, Srivastava S, Nazmutdinova J, den Ouden K, Zagers MS, Foletto V, Verhaar MC, Miles C, Sayer JA, Cimprich KA, Giles RH. DNA replication stress underlies renal phenotypes in CEP290-associated Joubert syndrome. Journal of Clinical Investigation 2015, 125(9), 3657-3666.
- Ramsbottom S, Miles C, Sayer J. Murine Cep290 phenotypes are modified by genetic backgrounds and provide an impetus for investigating disease modifier alleles. F1000 Research 2015, 4, 590.
- Srivastava S, Hynes AM, Miles C, Giles RH, Sayer JA. Studying mechanisms underlying cystogenesis in NPHP6 in an ex vivo murine collecting duct cell line. In: 52nd ERA-EDTA Congress. 2015, London, UK: Oxford University Press.
- Al-Ajmi N, Saretzki G, Miles C, Spyridopoulos I. Dietary restriction ameliorates haematopoietic ageing independent of telomerase, whilst lack of telomerase and short telomeres exacerbate the ageing phenotype. Experimental Gerontology 2014, 58, 113-119.
- Hynes AM, Giles RH, Srivastava S, Eley L, Whitehead J, Danilenko M, Raman S, Slaats GG, Colville JG, Ajzenberg H, Kroes HY, Thelwall PE, Simmons NL, Miles CG, Sayer JA. Murine Joubert syndrome reveals Hedgehog signaling defects as a potential therapeutic target for nephronophthisis. Proceedings of the National Academy of Sciences of the United States of America 2014, 111(27), 9893-9898.
- Cunningham TJ, Palumbo I, Grosso M, Slater N, Miles CG. WT1 regulates murine hematopoiesis via maintenance of VEGF isoform ratio. Blood 2013, 122(2), 188-92.