1 / 17

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

emi-perez
Download Presentation

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

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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.

More Related