WT1 and Wilms TumorJoshua Chen

Homozygous mutant mice are embryonic lethal and fail to develop kidneys and gonads, with additional defects in the heart, diaphragm, retina, olfactory epithelium, and spleen

Kreidberg, J., Sariola, H., Loring, J., Maeda, M., Pelletier, J., Houseman, D., Jaenisch, R.

WT1 encodes a developmentally regulated transcription factor

Rauscher, F

There are many isoforms of WT1 proteinwith different DNA and protein binding specificities

Hohenstein, P., Hastie, N.

Red represents alternative start codons, exons, RNA editing, and splicesGreen represents some functional sequences that may be excluded due to these processes

WT1 gene

36 or more possible WT1 protein isoforms

transcriptional up-regulation

transcriptional down-regulation

RNA splicing translation epigenetics

growth differentiation

epigeneticsapoptosis

Wilms tumor is the most common childhood kidney tumor and 20% have mutations in WT1

Normal kidney

Kidney with Wilm’s tumor

http://peir.path.uab.edu/wiki/File:IPLab13WT1.jpg

Nephrogenic rests are often found in these tumors and are precursors to tumor cells

Keeling, J.

WT1 regulates transcription of Wnt-4, a possible explanation for the role of WT1 in Wilms tumor

Sim, E., Smith, A., Szilagi, E., Rae, F., Ioannou, P., Lindsay, M., Little, M.

WT1 mutation in C2A

Wnt-4 is necessary for mesenchymal differentiation and nephrogenesis

+/+ or +/-

-/- -/-+/+ or +/-

Stark, K., Vainio, S., Vassileva, G., McMahon, A.

12.5 d.p.c. 14.5 d.p.c.

9 out of 10 Wilms tumors are successfully treated using surgery, chemotherapy, and radiation. Experimental targeted therapy includes WNT/β-Catenin Pathway Modulators.

http://mct.aacrjournals.org/content/12/12/2619.long

When overexpressed as in these cancers, WT1 can also acts as an oncogene

Yang, L., Han, Y., Saiz, F., Minden, M.

Summary

WT1 plays a crucial role in urogenital development

WT1 has a variety of isoforms that can act in various capacities, including acting as a transcription factor

In Wilms tumor, WT1 is a tumor suppressor that normally upregulates transcription of Wnt-4

In its absence, Wnt-4 fails to be expressed, the cells fail to differentiate, and eventually may become cancerous

In other tumors, WT1 has been shown to act as an oncogene

References

Hohenstein, P., Hastie, N. The many facets of the Wilm’s tumour gene, WT1. Human Molecular Genetics. 2006; 15: 196-201

Ozdemir, D., Hohenstein, P. Wt1 in the kidney—a tale in mouse models. Journal of the Pediatric Nephrology Association. 2013; 29: 687-693.

Sim, E., Smith, A., Szilagi, E., Rae, F., Ioannou, P., Lindsay, M., Little, M. Wnt-4 regulation by the Wilm’s tumour suppressor gene, WT1. Oncogene. 2002; 21: 2948-2960.

Stark, K., Vainio, S., Vassileva, G., McMahon, A. Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature. 1994.; 372: 679-683.

Tian, F., Yourek, G., Shi, X., Yang, Y. The development of Wilm’s tumor: From WT1 and microRNA to animal models. Biochimica et Biophysica Acta. 2014; 1846: 180-187.

Toska, E., Roberts, S. Mechanisms of transcriptional regulation by WT1 (Wilm’s tumour 1). Biochemical Journal. 2014; 461: 15-32. 

Yang, L., Han, Y., Saiz, F., Minden, M. A tumor suppressor and oncogene: the WT1 story. Leukemia. 2007; 21: 868-876.

Kreidberg, J., Sariola, H., Loring, J., Maeda, M., Pelletier, J., Houseman, D., Jaenisch, R. WT-1 is required for early kidney development. Cell. 1993; 74: 679-691.

Rauscher, F. The WT1 Wilms tumor gene product: a developmentally regulated transcription factor in the kidney that functions as a tumor suppressor. The FASEB Journal. 1993; 7: 896-903.

Keeling, Jean. Fetal and Neonatal Pathology. London: Springer-Verlag, 1987. Print.

Perotti, D., Hohenstein, P., Bongarzone, I, Maschietto, M., Weeks, M., Radice P., Prithard-Jones, K. Is Wilms Tumor a Candidate Neoplasia for Treatment with WNT/β-Catenin Pathway Modulators?—A Report from the Renal Tumors Biology-Driven Drug Development Workshop. Molecular Cancer Therapeutics. 2013; 12: 2619-2627.