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by Jennifer Mackey

by Jennifer Mackey. NEPHROBLASTOMA in children Discovered by Max Wilms in 1899 WT1 is a tumor suppressor 10-15% due to WT1 inactivation. Wilms’ Tumor. Kidney MRI. (Scott et al., 2001). BUT, MUTATED WT1 IS ALSO FOUND IN OTHER CANCERS!!. BUT, MUTATED WT1 IS ALSO FOUND IN OTHER CANCERS!!

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by Jennifer Mackey

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  1. by Jennifer Mackey

  2. NEPHROBLASTOMA in children • Discovered by Max Wilms in 1899 • WT1 is a tumor suppressor • 10-15% due to WT1 inactivation Wilms’ Tumor Kidney MRI (Scott et al., 2001)

  3. BUT, MUTATED WT1 IS ALSO FOUND IN OTHER CANCERS!!

  4. BUT, MUTATED WT1 IS ALSO FOUND IN OTHER CANCERS!! AND AS WE WILL SEE - IT IS NOT ALWAYS A TUMOR SUPPRESSOR!!!

  5. WT1 is alternatively spliced to make many protein isoforms (Wagner, K.D. et al., 2003)

  6. WT1 is a transcription factor (Exon 5) (Exon 9) (Scholz, H. et al., 2005)

  7. WT1 is a transcription factor

  8. WT1’s normal biological functions • Development of genitourinary system • Development of kidney • Adult kidney • Heart development • Neuron development?

  9. WT1 KNOCKOUT MICE • WT1-/- • dies E12-birth • no kidneys • no gonads • severe abnormalities of retinal development wt KO (Kreidberg et al., 1993)

  10. WT1 KNOCKOUT MICE • WT1-/- • dies E12-birth • no kidneys • no gonads • severe abnormalities of retinal development • WT1+/- • increased mortality due to adult onset nephrotic syndrome & renal failure

  11. WT1 is required for kidney development (Scholz, H. et al., 2005)

  12. ADULT KIDNEY http://en.wikipedia.org/wiki/Image:Gray1128.png

  13. WT1 is part of a transcriptional regulatory network That is critical for kidney development (Scharnhorst, V. et al., 2001)

  14. WT1 is part of a transcriptional regulatory network That is critical for kidney development (Scharnhorst, V. et al., 2001) • WT1 TARGET GENES INVOLVED IN KIDNEY DEVELOPMENT: • Amphiregulin: stimulates uretic bud • BCL-2: encodes antiapoptotic protein • E-cadherin: mesenchyme condensation

  15. WT1’s Role in Cancer REMEMBER: WT1 = differentiation

  16. WT1’s Role in Cancer WT1 = PROLIFERATION!!

  17. WT1 is a tumor suppressor • Wilms tumor • Most are sporadic and unilateral • 10-15% of sporadic have WT1 inactivation • Most others have high levels of WT1 expression • ~10% are bilateral and/or multifocal http://www.sainte-justine.org/

  18. WT1 is a tumor suppressor • Wilms tumor • Most are sporadic and unilateral • 10-15% of sporadic have WT1 inactivation • Most others have high levels of WT1 expression • ~10% are bilateral and/or multifocal • WAGR (Wilms’ tumor, Aniridia, Genitourinary abnormalities, Mental retardation) • Germline deletion • Predisposition to WT http://en.wikipedia.org/wiki/Image:BlackEyesAniridia.jpg

  19. WT1 is a tumor suppressor • Wilms tumor • Most are sporadic and unilateral • 10-15% of sporadic have WT1 inactivation • Most others have high levels of WT1 expression • ~10% are bilateral and/or multifocal • WAGR (Wilms’ tumor, aniridia, genitourinary abnormalities, mental retardation) • Germline deletion • Predisposition to WT • Denys-Drash Syndrome (DDS) • Germline mutations (missense mutation in zinc finger domain) • Dominant-negative activity • Predisposition to WT

  20. WT1 is a tumor suppressor • Wilms tumor • Most are sporadic and unilateral • 10-15% of sporadic have WT1 inactivation • Most others have high levels of WT1 expression • ~10% are bilateral and/or multifocal • WAGR (Wilms’ tumor, aniridia, genitourinary abnormalities, mental retardation) • Germline deletion • Predisposition to WT • Denys-Drash Syndrome (DDS) • Germline mutations (missense mutation in zinc finger domain) • Dominant-negative activity • Predisposition to WT • Frasier Syndrome • Germline point mutation in the intron 9 donor splicesite • Loss of KTS (-) = ratio disturbed • WT very rare!

  21. …and WT1 is an Oncogene! Acute myeloid leukemia(AML): WT1 overexpressed in leukemic blasts http://en.wikipedia.org/wiki/Image:Auer_rods.PNG

  22. …and WT1 is an Oncogene! Acute myeloid leukemia(AML): WT1 overexpressed in leukemic blasts Breast cancer: expression of WT1 detected in majority of BC’s evaluated www.hopeforcancer.com/BreastCancer.html

  23. …and WT1 is an Oncogene! Acute myeloid leukemia(AML): WT1 overexpressed in leukemic blasts Breast cancer: expression of WT1 detected in majority of BC’s evaluated Renal cell carcinoma: overexpression of WT1 in tubular epithelial cells in adulthood http://en.wikipedia.org/wiki/Image:RCC.jpg

  24. GOOD NEWS! 80% of tumors can be treated successfully!!!

  25. REFERENCES Kreidberg, Jordan A. et al. 1993. WT-1 Is Required for Early Kidney Development. Cell 74: 679-691. Loeb, David M. and Saraswati Sukumar. 2002. The Role of WT1 in Oncogenesis: Tumor Suppressor or Oncogene? International Journal of Hematology 76: 117-126. Scharnhorst, Volkher et al. 2001. WT1 proteins: functions in growth and differentiation. Gene 273: 141-161. Scholz, Holger and Karin M. Kirschner. 2005. A Role for the Wilms’ Tumor Protein WT1 in Organ Development. Physiology 20: 54-59. Scott, Carly M. et al. 2001. Wilms' Tumor: A Primary Care Case Study And Differential Diagnosis. The Internet Journal of Advanced Nursing Practice 5: Number 1. Wagner, K-D et al. 2003. The complex life of WT1. Journal of Cell Science 116: 1653-1658. Wagner et al. 2006. Intermediate filament protein nestin is expressed in developing kidney and heart and might be regulated by the Wilms’ tumor suppressor WT1. American Journal of Physical Regul Integr Comp Physiology 291: R779-R787.

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