Download Von Hippel-Lindau Syndrome

Von Hippel-Lindau Syndrome
VHL/HIF1
Meredith Meara
3-30-04
Von Hippel-Lindau Syndrome
VHL is a tumor suppressor
•80% familial
•20% sporadic
•Prevalent in
all ethnic
groups
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
VHL is a component of an E3
Ubiquitin Ligase Complex
I’m
an E3
Prolyls
 Asparagine
HIF 
Normoxia – Normal O
2
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
What about Hypoxic Conditions?
X
X
X
Hypoxia – Decreased O
X
2
X
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
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
VHL is modified too!
•Before VHL can bind/polyubiquinate
HIF, it must be modified
•CCT facilitates VHL and elongin
binding
•Cul2 has to be modified by Ubc12
then, it joins the Elongin VHL
complex
•This complex facilitates the
polyubiquitination of VHL
•The VHL complex is constructed
independent of oxygen level
The Big Picture
Under normal
O2 Conditions,
HIF is degraded
In Hypoxic
Conditions, HIF
is active
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
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
The End
Questions?