Wilms Tumour Protein Flashcards
What mutations occur in WAGR
Mainly nonsense mutation
Constituitional 11p13 deletions
What is the phenotype and mutation in Denys-Drash Syndrome
Pseudohermaphrodism, nephropathy and predisposition to Wilms tumour
Mainly missense mutation in ZF domain and promoter truncations
What mutations often occur in leukaemia regarding Wt1
Mutations small insertions on exons 1 & 7
What mutations often occur in desmoplastic round cell tunmours and WT1
mainly EWS fusion proteins with Zinc Fingers 2 -4
Produces a phenotypically immature tumour tumour with a higher odds in young males
when is wt1 involved in EMT
Heart vasculatore formation
When is wt1 invovled in MET
IN kidney and gonad development
How does WT1 regulate EMT
Activates SNAIL and directly represses E-Cadherin
What does WT1 regulate to control adult tissue homeostasis
IGF2
What occurs if you get WT1 knockout in adult mice
Die after 9 days
Often display loss of visceral fat and bone
Also get pancreatic atrophy and renal atrophy
what lieage of cells is wt1 particularly important to maintain
Haematopoeitic cells
If you lose wt1 what type of fat do you lose and what type do you keep
Lose visceral fat
However wt1 not detected in subcutaneous and BAT fat hence these arent affected
Describe the structure of WT1
Very complex gene
10 exons, at least 36 isorforms
4 main isoforms are +/-KTS splice variant and +/- exon 5 par4 binding domain
Has 4 Zn fingers all in seperate exons
What is the antisense of WT1 called
AWT1
What is towards the N terminus of WT1
a dimerization domain
Transactivation domain
transrepression domain
How do phosphorylation and sumolytion affect WT1
Phosphorylation of WT1 zinc fingers however doesnt affect nuclear localisation
Sumolyation DOES affect nuclear localisation and instead WT1 often found with splice factors
What proteins interact with WT1
WTX –> wilms tumour associated protein
STAT3
BASP1
HtrA2
What is the interaction of HtrA2 and WT1
Interacts with the suppression domain
Cleaves WT1 in several places
Makes more oncogenic forms of WT1
What genes does normal WT1 repress
hTERT
Cyclin E
bcl-2
What genes does normal WT1 induce
E-Cadherin
p21
How does WT1 act in regards to Wnt4 in the kidney
Induces Wnt4
Recurits CBP/p300 coactivators
How does WT1 act in regards to Wnt4 in the epicardium
Binds wnt4, recruits repressors e.g. BASP1
What is the key regulator for kidney development
WNT4 that is at least partially transcriptionally regulated by Wt1
What is the role of WT1 in RNA metabolism
+KTS Splice isoforms co localise in speckles, coiled bodies and nuclear bodies and are inovlved in RNA splicing
What do Wt mutations often occur with
GOF of Beta catenin
How many isoforms of Wt1 do non-mammals have
2 only have the +/- KTS isoforms
Describe the mechanism of mutant Wt1 in Denys-Drash syndrome
Operates in a dominant-negative fashion –> where the mutant Wt can dimerise with the WT proteins
What occurs in Meachan syndrome
CHD renal abnormalities
What is necessary AND sufficient to undce MET in the metanephric mesenchyme
Wnt4
What is wnt essential for in adult life
The maintenenance and differentiation of podocyte cells
What is Wt fucntions in kidney development
Target genes for kidney development: PAX2, Sal< BMP7, Wnt4
Target genes for mesenchyme proliferation: Induces FGFs and represses BMP/SMAD signalling
Why is Wt1 essential for diaphragm formation
Wt1 is needed to induce EMT in the post hepatic plate coleomic epithelium –> if defective then get congential diaphragmatic hernias
How is Wt1 essential in sertoli cells
Cooperates with GATA4 to activate SRY which underlies Sertoli cell development
What happens to Wt1 following cardiac ischaemia
Can be reactivated to produce new EPDCs whcih could give rise to new cardiac vasculature
What happen sif you delete Wt1 in adults
Death due to loss of bone and visceral fat and severe glomeruosclerosis
What can induce Wt1 in hypoxia
HIF-1 –> therefore there coudl be a potential role of exploiting Wt1 to respond to ischaemia
How does Wt1 -KTS isoforms affect DNA
Bidns to DNA - first Zn finger just adds stability
can act as an activator or repressor depending on partner
How can wt1 affect epigenetics
Can increases TET2 enzyme
How does Wt1 bind to RNA
THe +KTS isoform –> idning does require the first Zn finger. Affets RNA stability and splicing
Also binds to Wilms Tumour Associated Protein
What can WT1 also contol regarding RNa Pol II
Can control the differential occupancy of RNA PolIII relative to the Wnt4 transcritpional start site –> i.e. elongating PolII wnt TSS in kidney but stalling in the epicardium
What does the chromatin flip flop refer to
Refers to the domain wide chromatin switch, rather than just the differential bidning of Wt1 to Wnt4 and this can determine the outcome of Wt1 action.
