WT1: Wilms’ Tumor gene
by Jennifer Mackey
Kidney MRI
(Scott et al., 2001)
Wilms’ Tumor
o NEPHROBLASTOMA in children
o Discovered by Max Wilms in 1899
oWT1 is a tumor suppressor
o10-15% due to WT1 inactivation
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
Growth factor
Amphiregulin
Insulin growth factor II
Platelet derived growth factor
Transforming growth factor-beta
Receptors
Androgen receptor
Epidermal growth factor receptor
Insulin receptor
Insulin growth factor – I receptor
Transcription factor
c-Myc
Cyclin E
Cyclin G1, IGFBP-4
P21
Pax-2
Enzymes
Effect
Activation
Activation/repression
Repress/act
Repression
Repression
Repression
Repression
Repression
Activation/repression
Repression
Activation
Activation
Repression
Human telomerase reverse transcriptase
Repression
Ornithine decarboxylase
ECM
E-cadherin
Syndecan-1
Other
Wnt-4
Repression
Bcl-2
Activation/repression
Increased
Activation
Activation
WT1’s normal biological functions
o
o
o
o
o
Development of genitourinary system
Development of kidney
Adult kidney
Heart development
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.