WT1: Wilms’ Tumor gene

by Jennifer Mackey
o NEPHROBLASTOMA in children
o Discovered by Max Wilms in 1899

Wilms’ Tumor
oWT1 is a tumor suppressor
o10-15% due to WT1 inactivation

Kidney MRI
(Scott et al., 2001)
BUT, MUTATED WT1 IS ALSO FOUND IN OTHER
CANCERS!!
BUT, MUTATED WT1 IS ALSO FOUND IN OTHER
CANCERS!!

AND AS WE WILL SEE - IT IS NOT ALWAYS A

TUMOR SUPPRESSOR!!!
WT1 is alternatively spliced to make many
protein isoforms

(Wagner, K.D. et al., 2003)

WT1 is a transcription factor

(Exon 5) (Exon 9)

(Scholz, H. et al., 2005)

WT1 is a transcription factor
Target Effect
Growth factor
Amphiregulin Activation
Insulin growth factor II Activation/repression
Platelet derived growth factor Repress/act
Transforming growth factor-beta Repression
Receptors
Androgen receptor Repression
Epidermal growth factor receptor Repression
Insulin receptor Repression
Insulin growth factor – I receptor Repression
Transcription factor
c-Myc Activation/repression
Cyclin E Repression
Cyclin G1, IGFBP-4 Activation
P21 Activation
Pax-2 Repression
Enzymes
Human telomerase reverse transcriptase Repression
Ornithine decarboxylase Repression
ECM
E-cadherin Increased
Syndecan-1 Activation
Other
Wnt-4 Activation
Bcl-2 Activation/repression
WT1’s normal biological functions

o Development of genitourinary system

o Development of kidney
o Adult kidney
o Heart development
o Neuron development?
WT1-/-
• dies E12-birth
• no kidneys
• no gonads
•severe abnormalities of retinal development

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

WT1+/-
• increased mortality due to adult onset nephrotic
syndrome & renal failure
WT1 is required for kidney development

(Scholz, H. et al., 2005)

ADULT KIDNEY

http://en.wikipedia.org/wiki/Image:Gray1128.png
WT1 is part of a transcriptional regulatory network
That is critical for kidney development

(Scharnhorst, V. et al., 2001)

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

REMEMBER: WT1 = differentiation
WT1 = PROLIFERATION!!
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/
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
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
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 splice site
•Loss of KTS (-) = ratio disturbed
•WT very rare!
Acute myeloid leukemia(AML): WT1 overexpressed in leukemic blasts

http://en.wikipedia.org/wiki/Image:Auer_rods.PNG
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
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
80% of tumors can be treated successfully!!!
 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.