Wilms’ Tumor Nephroblastoma Affects 1:10,000 children ~8% of all pediatric Malignancies 80% of...

Wilms’ Tumor

Nephroblastoma Affects 1:10,000 children ~8% of all pediatric Malignancies 80% of these tumors can be successfully

treated

WT1 Tumor Suppressor Chromosome 11 (11p13) Mutated in 5-10% of all Wilms Tumors ~50Kb 10 exons 52-62 kDa 24 Isoforms

WT1

Scholz et al.

WT1

Wagner et al.

Frasier Syndrome

Heterozygous loss of +KTS causes

• Male to Female sex reversal

• Wilms’ Tumor

• Glomerulosclerosis

WAGR SyndromeHeterozygous loss of WT1 Wilms’ Tumor Mental retardation Milder overall phenotype in kidneys and

gonads than DDS and FS

Denys-Drash Syndrome

Truncated Zinc-Fingers

Causes

• normal female gonads

• In males, streak gonads and mild hermaphroditism

• Wilm’s Tumor

Dominant-negative phenotype

Denys-Drash Syndrome

• Wild type WT1 homodimerizes

• Truncated WT1 dimerizes with wild type WT1, which further lowers WT1 function

• Truncated WT1 works in a Dominant-Negative motif

Knockout Mice Embryonic Lethal between 12 days and birth Mice had no Kidneys nor Gonads and defects in

mesothelial tissue, heart, adrenal glands and spleen WT1(+KTS) lacking Mice showed disturbed podocyte

function and male-to-female sex reversal WT1 (-KTS) lacking Mice showed severe kidney and

gonad defects

WT1

Wagner et al.

In Conclusion WT1 is a Tumor Suppressor WT1 has 24 Isoforms WT1 interacts with DNA, RNA and other Proteins WT1 is a Transcription Factor It is an Enhancer It is a Developmental Gene

ReferencesScharnhorst, V., Van der Eb, A., Jochemsen, A. 2001. WT1 proteins:

funtion in growth and differentiation. Gene: 273, p141-161.

Scholz, H., Kirschner, K. 2005. A Role for the Wilm’s Tumor Protein WT1 in Organ Development. Physiology 20: p54-59.

Wagner, K-D., Wagner, N., Schedl, A. 2003. The complex life of WT1. Journal of Cell Science: p1653-1658