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WT1 and Wilms’ Tumor: The Fine Line between Normal Development and Cancer

WT1 and Wilms’ Tumor: The Fine Line between Normal Development and Cancer. Christine J. Chung BIOL 169. What is WT1 ?. Tumor suppressor gene Spans ~ 50 kb and 10 exons Encodes a zinc-finger transcription factor 24 isoforms with partially distinct but also overlapping biological functions

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WT1 and Wilms’ Tumor: The Fine Line between Normal Development and Cancer

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  1. WT1 and Wilms’ Tumor:The Fine Line between Normal Development and Cancer Christine J. Chung BIOL 169

  2. What is WT1? • Tumor suppressor gene • Spans ~ 50 kb and 10 exons • Encodes a zinc-finger transcription factor • 24 isoforms with partially distinct but also overlapping biological functions • Alternative splicing, RNA editing, and initiation of translation at variable start sites

  3. Structure of WT1 and its protein product

  4. WT1 and congenital abnormalities • Denys-Drash Syndrome • Frasier Syndrome • WAGR (Wilms’ tumor, aniridia, genitourinary abnormalities, mental retardation) Syndrome • Beckwith-Wiedemann Syndrome • CONCLUSION: WT1 must play a role in normal embryonic development…

  5. Normal embryonic development of the kidney Moore KL and Persaud TVN, 1993

  6. WT1’s role in early kidney development • Normal kidney forms through interactions between the ureteric epithelium and the metanephric mesenchyme • WT1 may be necessary to make the mesenchyme competent to form tubules http://ase.tufts.edu/biology/labpages/kelly/images/uploaded/kidney_3_parts.jpg

  7. WT1 pathway in nephrogenesis WT1 PAX2 WT1 amphiregulin PAX8 Ureteric bud branching NEPHRON

  8. Gene expression patterns in early developing kidney http://herkules.oulu.fi/isbn9514269918/html/c341.html#AEN351

  9. Studies in WT1-/- Knockout Mice • Embryonic lethal • Increased apoptosis in many organs e.g. gonads, kidneys, and spleen • Failure of kidney and gonad development • Day 11:the metanephric blastema undergoes apoptosis • Ureteric bud fails to grow out from the Wolffian duct • Inductive events that normally form metanephric kidney fail to occur

  10. Studies in Heterozygous WT1+/- Mice • Adult onset kidney disease • Onset dependent on degree of reduction in WT1 expression • Also increased risk of kidney failure in human patients heterozygous for WT1 mutations

  11. What does WT1 normally do? • Embryonic development – early urogenital and kidney development, sex determination • Expressed in certain cells through adulthood; e.g. podocytes of the kidneys • Maintains organ function http://edcenter.med.cornell.edu/Pathology_Images/180.gif

  12. What is Wilms’ tumor? • Pediatric kidney cancer • Thought to occur when pluripotent mesenchymal cells in developing kidney continue to proliferate instead of differentiating into the appropriate renal structures • Affects 1:10,000 children, usually before age 5 • 400-500 new cases in the U.S. each year • Accounts for 7.5% of all childhood tumors

  13. More about Wilms’ tumor • Usually affects only one kidney • Only ~ 5% of cases are bilateral • More common among black children and females • The average weight of a newly discovered Wilms’ tumor is 1 pound

  14. Untreated Wilms’ tumor www.haydom.no/en/theatre.htm

  15. WT1 and Wilms’ tumor • ~10% of all Wilms’ tumors have a loss of function mutation in the WT1 gene • Familial Wilms’ tumor only accounts for 1% of all cases • Alterations in WT1 are also observed in other tumor types e.g. leukemia

  16. Treatment and Prognosis • Surgery to remove tumor or affected kidney • Chemotherapy and sometimes radiation • 85% can be successfully treated

  17. References • Mrowka, C. and Schedl, A. (2000). Wilms’ tumor suppressor gene WT1: from structure to renal pathophysiologic features. J. Am. Soc. Nephro. 11, S106-S115. • Rauscher III, F.J. (1993). The WT1 Wilms tumor gene product: a developmentally regulated transcription factor in the kidney that functions as a tumor suppressor. FASEB J. 7, 896-903. • Scharnhorst, V., van der Eb, A.J. and Jochemsen, A.G. (2001). WT1 proteins: functions in growth and differentiation. Gene273, 141-161. • Scholz, H. and Kirschner, K.M. (2005). A role for the Wilms’ tumor protein WT1 in organ development. Physiology20, 54-59. • Wagner, K.D., Wagner, N. and Schedl, A. (2003). The complex life of WT1. J. Cell Sci. 116, 1653-1658.

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