Skip to content

Research at St Andrews

Multiple roles for the Wilms' tumor suppressor, WT1

Research output: Contribution to journalReview articlepeer-review

Author(s)

R Davies, A Moore, A Schedl, E Bratt, K Miyahawa, M Ladomery, C Miles, A Menke, V van Heyningen, N Hastie

School/Research organisations

Abstract

Wilms' tumor is a childhood kidney tumor that is a striking example of the way that cancer may arise through development gone awry. A proportion of these tumors develop as a result of the loss of function mutations in the Wilms' tumor suppressor gene, WT1. Inherited mutations in the WT1 gene can lead to childhood kidney cancer, severe gonadal dysplasia, and life-threatening hypertension. Knockouts show that the gene is essential for the early stages of kidney and gonad formation. These tissues are completely absent in null mice. The WT1 gene encodes numerous protein isoforms, all of which share four zinc fingers. There is a large body of evidence supporting the notion that WT1 is a transcription factor, particularly a transcriptional repressor. Recently, however, we obtained evidence that WT1 colocalizes and is physically associated with splice factors. What is more, one alternative splice isoform of WT1 containing three amino acids, Lys-Thr-Ser (KTS; inserted between zinc fingers 3 and 4) is preferentially associated with splice factors, whereas the other alternative splice version, lacking these three amino acids, preferentially associates with the transcriptional apparatus. Both genetic and evolutionary considerations suggest that these two different forms of the protein have different functions. We will discuss recent evidence to further implicate WT1 in splicing. Our results raise the possibility that regulation of splicing is a crucial factor in the development of the genitourinary system, and that tumors may arise through aberrant splicing. To pursue the regulation and function of WT1 in whole animals, we have been introducing the human gene and large flanking regions cloned in yeast artificial chromosomes directly into mice. These studies have allowed us to dissect the function of WT1 at late as well as at early stages in organogenesis and to identify new sites and surprising new potential functions for the gene.

Close

Details

Original languageEnglish
Pages (from-to)1747s-1750s; discussion 1751s
JournalCancer Research
Volume59
Issue number7 Suppl
Publication statusPublished - 1 Apr 1999

    Research areas

  • Alternative Splicing, Animals, Chromosomes, Artificial, Yeast, Genes, Tumor Suppressor, Genes, Wilms Tumor, Humans, Transcription, Genetic

Discover related content
Find related publications, people, projects and more using interactive charts.

View graph of relations

Related by author

  1. Association of human papillomavirus 16 E2 with Rad50-interacting protein 1 enhances viral DNA replication

    Campos-León, K., Wijendra, K., Siddiqa, A., Pentland, I., Feeney, K. M., Knapman, A., Davies, R., Androphy, E. J. & Parish, J. L., Mar 2017, In: Journal of Virology. 91, 5, 18 p., e02305-16.

    Research output: Contribution to journalArticlepeer-review

  2. Stabilization of stalled DNA replication forks by the BRCA2 breast cancer susceptibility protein

    Lomonosov, M., Anand, S., Sangrithi, M., Davies, R. & Venkitaraman, A. R., 15 Dec 2003, In: Genes & Development. 17, 24, p. 3017-22 6 p.

    Research output: Contribution to journalArticlepeer-review

  3. Identification of WTAP, a novel Wilms' tumour 1-associating protein

    Little, N. A., Hastie, N. D. & Davies, R. C., 22 Sep 2000, In: Human Molecular Genetics. 9, 15, p. 2231-9 9 p.

    Research output: Contribution to journalArticlepeer-review

  4. Did nucleotides or amino acids drive evolutionary conservation of the WT1 +/-KTS alternative splice?

    Davies, R. C., Bratt, E. & Hastie, N. D., 1 May 2000, In: Human Molecular Genetics. 9, 8, p. 1177-83 7 p.

    Research output: Contribution to journalArticlepeer-review

  5. WT1 interacts with the splicing factor U2AF65 in an isoform-dependent manner and can be incorporated into spliceosomes

    Davies, R. C., Calvio, C., Bratt, E., Larsson, S. H., Lamond, A. I. & Hastie, N. D., 15 Oct 1998, In: Genes & Development. 12, 20, p. 3217-25 9 p.

    Research output: Contribution to journalArticlepeer-review

Related by journal

  1. Diagnostic accuracy of quantitative micro-elastography for margin assessment in breast-conserving surgery

    Kennedy, K. M., Zilkens, R., Allen, W. M., Foo, K. Y., Fang, Q., Chin, L., Sanderson, R. W., Anstie, J., Wijesinghe, P., Curatolo, A., Tan, H. E. I., Morin, N., Kunjuraman, B., Yeomans, C., Chin, S. L., DeJong, H., Giles, K., Dessauvagie, B. F., Latham, B., Saunders, C. M. & 1 others, Kennedy, B. F., Apr 2020, In: Cancer Research. 80, 8, p. 1773-1783 11 p.

    Research output: Contribution to journalArticlepeer-review

  2. The impact of early lapatinib-induced rash on disease-free and overall survival in patients treated within the ALTTO phase Ill randomized trial

    Azim, H. A., Sonnenblick, A., Agbor-Tarh, D., Bradbury, I., Daly, F., Huang, Y., Dueck, A. C., Pritchard, K., Wolff, A. C., Jackisch, C., Lang, I., Untch, M., Smith, I., Boyle, F., Xu, B., Gomez, H., Perez, E., Piccart, M. & de Azambuja, E., 15 Feb 2016, In: Cancer Research. 76, 2 p.

    Research output: Contribution to journalAbstractpeer-review

  3. Investigation of optical coherence microelastography as a method to visualize cancers in human breast tissue

    Kennedy, B. F., McLaughlin, R. A., Kennedy, K. M., Chin, L., Wijesinghe, P., Curatolo, A., Tien, A., Ronald, M., Latham, B., Saunders, C. M. & Sampson, D. D., 15 Aug 2015, In: Cancer Research. 75, 16, p. 3236-3245 10 p.

    Research output: Contribution to journalArticlepeer-review

  4. Correction: Physical oncology: A bench-to-bedside quantitative and predictive approach

    Frieboes, H. B., Chaplain, M. A. J., Thompson, A. M., Bearer, E. L., Lowengrub, J. S. & Cristini, V., 1 Mar 2011, In: Cancer Research. 71, 5, p. 2024 1 p.

    Research output: Contribution to journalArticlepeer-review

  5. Physical oncology: a bench-to-bedside quantitative and predictive approach

    Frieboes, H. B., Chaplain, M. A. J., Thompson, A. M., Bearer, E. L., Lowengrub, J. S. & Cristini, V., 15 Jan 2011, In: Cancer Research. 71, 2, p. 298-302 5 p.

    Research output: Contribution to journalArticlepeer-review

ID: 260532943

Top