1. pVHL and von Hippel-Lindau Disease Tanner Fadero BIOL 445 April 14, 2015

2. paradigm

3. questions

4. pVHL is part of an E3 ubiquitin ligase complex 2 1

5. pVHL binds and ubiquitylates HIF-α to target for degradation 3 OH U U U U polyubiquitylation proteosome degradation

6. HIF-α remains undegraded in hypoxia, dimerizes, and forms TF Minutes exposed to 20% O 2 H1F - Hours exposed to 1% O 2 Hypoxia (inhibition of hydroxylases) 4 OH Transcription Factor VEGF Phosphoglycerate Kinase Glut-1 Erythropoietin

7. VHL -/- mutants are embryonic lethal due to vasculature malformation D. melanogaster embryos WT ds d-VHL RNA 5 Mice embryos Day E10.5 WT VHL -/- 6

8. Heterozygous/conditional VHL knockouts cause hemangiomas in mice 6 VHL 1/+ (heterozygous) mice Albumin-cre mutant mice liver cells

9. Kidney VHL knockouts in mice cause pre-cancerous phenotypes 7

10. Human VHL Disease is characterized by vascular tumors in many tissues 8

11. References 1.Hsu T. (2012) Complex cellular functions of the von Hippel–Lindau tumor suppressor gene: insights from model organisms. Oncogene 31: 2247-2257. 2.Pause A, Lee S, Worrell RA, Chen DY, Burgess WH, Linehan WM et al. (1997). The von Hippel-Lindau tumor- suppressor gene product forms a stable complex with human CUL-2, a member of the Cdc53 family of proteins. Proc. Natl. Acad. Sci. USA 94: 2156–2161. 3.Min J, Yang H, Ivan M, Gertler F, Kaelin WG, Pavletich, NP. (2007) Structure of an HIF-1–pVHL Complex: Hydroxyproline Recognition in Signaling. Science 296: 1886-1889. 4.Wang GL, Jiang B, Rue EA, Semenza GL. (1995) Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O 2 tension. Proc. Natl. Acad. Sci. USA 92: 5510-5514. 5.Adryan B, Decker HJ, Papas TS, Hsu T. (2000). Tracheal development and the von Hippel-Lindau tumor suppressor homolog in Droso- phila. Oncogene 19: 2803–2811. 6.Gnarra JR, Ward JM, Porter FD, Wagner JR, Devor DE, Grinberg A et al. (1997). Defective placental vasculogenesis causes embryonic lethality in VHL-deficient mice. Proc. Natl. Acad. Sci. USA 94: 9102–9107. 7.Rankin EB, Tomaszewski JE, Haase VH. (2006) Renal Cyst Development in Mice with Conditional Inactivation of the von Hippel-Lindau Tumor Suppressor. Cancer Research 66 (5): 2576-2583. 8.Maher ER, Neumann HPH, Richard S. (2011) von Hippel-Lindau disease: a clinical and scientific review. Eur. J. Hum. Genet. 19 (6): 617-623.