1. Von Hippel-Lindau Syndrome (VHL) Presented by Kelley Montoya March 20, 2003

2. Objectives VHL—Description of the disease Biochemistry VHL Conditions of normal VHL Mutations and Effects of VHL

3. What is VHL ? Dominantly inherited cancer syndrome Predisposition to tumors of the: Eyes Central Nervous System (CNS) Kidneys Adrenal Chromaffin cells

4. What is VHL? Tumor suppressor gene On cellular level it works as a simple recessive Inherited as an autosomal dominant Affects an estimated 1 in 36,000 people Mean onset age is 26.3 with a penetrance o 97% by age 60

5. What is VHL?

6. Clear Cell Carcinoma Normal cellsCancer cells

7. Biochemistry of VHL Mapped to Chromosome 3 in the region 3p25-p26 Encodes a protein called pVHL consisting of 213 amino acids Is a component of an protein complex known as an E3 ubiquitin ligase What do action do ubiquitin ligases perform?

8. Biochemistry of VHL This complex ubiquitinates HIF-1α (Hypoxia Inducible Factor), and leads to is subsequent proteosomal degradation HIF-1α is a transcription factor that promotes other transcription factors (esp VEGF) Loss of Function of pVHL leads to stabilization of HIF-1α (transcription factor) even under normoxic conditions (normal oxygen presence) What is hypoxia?

9. Biochemistry of VHL Conditions of Under Normal VHL Production

10. Biochemistry of VHL Under normoxic conditions HIF-1α is constantly being degraded Under anoxic conditions (low oxygen) HIF-1α is not destroyed leading to activation of transcription factors such as GLUT-1, PDGF-B and VEGF (vascular endothelial growth factor)

11. Mutations in pVHL Mutations usually occur in the two protein binding domains of VHL, either α and β Mutations include Missense, frameshift nonsense and splice junction mutations

12. Effects of VHL Over production of HIF-1α induces transcription factors involved in angiogenesis (growth of blood vessels) Thus sufferers of VHL develop highly vascularized tumors