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 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

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

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 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

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

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?