1. Von Hippel-Lindau Syndrome
VHL/HIF1
Meredith Meara

2. Von Hippel-Lindau Syndrome

3. VHL is a tumor suppressor
80% familial
20% sporadic
Prevalent in all ethnic groups

4. What does VHL do? VHL is very highly conserved evolutionarily
Homologs have been found in Drosophila, Mice, Rats, C. Elegans, BUT…not yeast
VHL loss of function during Drosophila development results in a ventral midline defect
Found high levels of VHL experession, during rat embryogenesis, in urogenital system, brain, spinal cord, sensory ganglia, eyes, and bronchial epithelium
Initial results suggested that it played a role in exiting the cell cycle

5. VHL is a component of an E3 Ubiquitin Ligase Complex
I’m an E3
Prolyls
 Asparagine
HIF 
Normoxia – Normal O2 conditions
HIF1 is hydroxylated on amino acid residues
Prolyl
Asparagine
When hydroxylated, HIF1 binds VHL
VHL polyubiquitinates HIF1
HIF1 is degraded, and prevented from performing normal activity

6. What about Hypoxic Conditions?
X X X
Hypoxia – Decreased O2 levels
HIF1 is not hydroxylated
VHL Cannot bind HIF
VHL doesn’t polyubiquitinates HIF1
HIF1 left in its active form, able to perform its necessary function
ACTIVE HIF

7. What does HIF do when it is active?
HIF is a transcription factor
HIF regulates TONS  of target genes, many of which are growth factors, and control angiogenesis

8. VHL is modified too!
Before VHL can bind/polyubiquinate HIF, it must be modified
This complex facilitates the polyubiquitination of VHL
CCT facilitates VHL and elongin binding
The VHL complex is constructed independent of oxygen level
Cul2 has to be modified by Ubc12 then, it joins the Elongin VHL complex

9. The Big Picture In Hypoxic Conditions, HIF is active
Under normal O2 Conditions, HIF is degraded

10. So what does VHL have to do with Cancer?
VHL inhibits HIF in normoxic conditions, but in hypoxic conditions HIF becomes active
Mutant VHL is a loss of function mutation, so in essence VHL is not existent
VHL can no longer inhibit HIF under any circumstances
A normal HIF gene will respond to VHL’s absence with an inappropriate hyperactive response to normal O2 levels
HIF will initiate tumor growth as well as proliferation via VEGF, TGF-a, PDGF – all of which are normally hypoxia inducible genes

11. What are possible treatment options?
Investigation is necessary for possible use of agents that are directed against HIF-responsive growth factors, and their cognate receptors
Some evidence that VEGF inhibitor can cause improvement in VHL patients
Most Research is in preliminary phases at this point; VHL has shown a previously unacknowledged role for enzymatic protein hydroxylation in intracellular signaling

12. The End
Questions?