wt1 Flashcards
What does WT1 gene do in normal cells?
- induces Wnt4
- induces MET and differentiation
- TSG
What pathway + gene mutations are often seen in Wilm’s tumour? (5)
- WT1
- MYCN
- miRNA processing proteins
- Let-7 pathways
- imprinting loss and methylation
What diseases are associated with aberrations in the WT1 gene? (4)
Wilm’s tumour: 11p13 deletions
Leukaemias: insertions
Desmoplastic small round cell tumours: fusion proteins
Mesothelioma: missense mutations caused by asbestos
How do we know WT1 is involved in development and TSG activity?
- mouse embryos with homozygous WT1 deletions have renal abnormalities and embyronic lethality
- adult mice with homozygous deletions die within 9 days
- 10-20% of Wilm’s tumours have WT1 mutations and/or deletions
- WT1 can repress colony formation and delay tumour formation in culture
What non-cancer diseases can WT1 be seen mutated in?
- tissue fibrosis
- congenital heart disease
Where in EMT is WT1 expressed?
- in the middle stages - in the stemness window
- not really expressed in epithelial cells
- controls SNAIL and e-cadherin to allow MET and differentiation of cardiovascular progenitor cells
How do we know that WT1 is required for adult tissue homeostasis?
How does it do this?
- paracrine and autocrine signalling
- control of systemic factors such as GFs and interleukins
- when haematopoetic cells are lost WT1 is required to produce common myeloid progenitors from stem cells
What is the role of WT1 in fat cells?
maintains the white adipose identity of visceral fat
How is WT1 expression location associated with cancer?
- for each location that WT1 is expressed there is an associated cancer
- metanephros - Wilm’s tumour
- mesothelial cells - mesothelioma
- endothelial cells - vascular tumours
Describe the structure of the WT1 protein
- multiple isoforms
- zinc finger binding domain - phosphorylation of which determines binding to RNA or DNA
- DNA binding proteins
- activation and repression domains
- +127 AUG start codon seen normally
- -69CUG start site seen in cancer
How many isoforms does WT1 have?
How and why?
- 36 sense, 12 antisense
- sense and antisense mRNA is alternatively spliced
- allows expression in kidney, mesothelial lining, uterus, brain etc
- allows involvement in EMT and MET
Give 2 proteins that interact with WT1 and where
- SRY male sex determining gene interacts only at zinc fingers
- STAT3 stemness marker interacts anywhere but the zinc fingers
Name 2 TFs usually repressed by WT1 and what happens if WT1 function is lost and they are therefore active
IFG2 - wilm’s tumour growth
hTERT - uncontrolled telomere lengthening
Name 2 TFs usually activated by WT1 and what happens if WT1 function is lost and they are therefore inactive
E-cadherin - increased invasiveness and decreased differentiation
p21 - loss of cell cycle control
How is WT1 involved in normal kidney development?
- where MET occurs (in the kidney), WT1 binds site of the Wnt4 locus and brings in CBP activator to increase Wnt4 expression
- where EMT occurs (in the epicardium) WT1 binds the same sites but brings in Basp1 repressors
