pVHL and von Hippel-Lindau Disease

Tanner Fadero

BIOL 445

April 14 2015

paradigm

questions

pVHL is part of an E3 ubiquitin ligase complex

21

pVHL binds and ubiquitylates HIF-α to target for degradation

3

OH

OH

OH

OH

U

U

UU

polyu

biquit

ylatio

n

proteosomedegradation

HIF-α remains undegraded in hypoxia dimerizes and forms TF

Minutes exposed to 20 O2

H1F-

Hours exposed to 1 O2

Hypoxia

(inhibition of hydroxylases)

4

OHOH

Transc

riptio

n

Factor

VEGFPhosphoglycerate Kinase

Glut-1Erythropoietin

VHL-- mutants are embryonic lethal due to vasculature malformation

D melanogaster embryos

WT

ds d

-VH

L R

NA

5 Mice embryos Day E105

WT

VH

L--

6

Heterozygousconditional VHL knockouts cause hemangiomas in mice

6

VHL1+ (heterozygous) mice Albumin-cre mutant mice liver cells

Kidney VHL knockouts in mice cause pre-cancerous phenotypes

7

Human VHL Disease is characterized by vascular tumors in many tissues

8

References1 Hsu T (2012) Complex cellular functions of the von HippelndashLindau 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 2156ndash2161

3 Min J Yang H Ivan M Gertler F Kaelin WG Pavletich NP (2007) Structure of an HIF-11113097ndashpVHL 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 O2 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 2803ndash2811

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 9102ndash9107

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

• pVHL and von Hippel-Lindau Disease
• paradigm
• questions
• pVHL is part of an E3 ubiquitin ligase complex
• pVHL binds and ubiquitylates HIF-α to target for degradation
• HIF-α remains undegraded in hypoxia dimerizes and forms TF
• VHL-- mutants are embryonic lethal due to vasculature malforma
• Heterozygousconditional VHL knockouts cause hemangiomas in mic
• Kidney VHL knockouts in mice cause pre-cancerous phenotypes
• Human VHL Disease is characterized by vascular tumors in many t
• References

paradigm

questions

pVHL is part of an E3 ubiquitin ligase complex

21

pVHL binds and ubiquitylates HIF-α to target for degradation

3

OH

OH

OH

OH

U

U

UU

polyu

biquit

ylatio

n

proteosomedegradation

HIF-α remains undegraded in hypoxia dimerizes and forms TF

Minutes exposed to 20 O2

H1F-

Hours exposed to 1 O2

Hypoxia

(inhibition of hydroxylases)

4

OHOH

Transc

riptio

n

Factor

VEGFPhosphoglycerate Kinase

Glut-1Erythropoietin

VHL-- mutants are embryonic lethal due to vasculature malformation

D melanogaster embryos

WT

ds d

-VH

L R

NA

5 Mice embryos Day E105

WT

VH

L--

6

Heterozygousconditional VHL knockouts cause hemangiomas in mice

6

VHL1+ (heterozygous) mice Albumin-cre mutant mice liver cells

Kidney VHL knockouts in mice cause pre-cancerous phenotypes

7

Human VHL Disease is characterized by vascular tumors in many tissues

8

References1 Hsu T (2012) Complex cellular functions of the von HippelndashLindau 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 2156ndash2161

3 Min J Yang H Ivan M Gertler F Kaelin WG Pavletich NP (2007) Structure of an HIF-11113097ndashpVHL 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 O2 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 2803ndash2811

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 9102ndash9107

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

• pVHL and von Hippel-Lindau Disease
• paradigm
• questions
• pVHL is part of an E3 ubiquitin ligase complex
• pVHL binds and ubiquitylates HIF-α to target for degradation
• HIF-α remains undegraded in hypoxia dimerizes and forms TF
• VHL-- mutants are embryonic lethal due to vasculature malforma
• Heterozygousconditional VHL knockouts cause hemangiomas in mic
• Kidney VHL knockouts in mice cause pre-cancerous phenotypes
• Human VHL Disease is characterized by vascular tumors in many t
• References

questions

pVHL is part of an E3 ubiquitin ligase complex

21

pVHL binds and ubiquitylates HIF-α to target for degradation

3

OH

OH

OH

OH

U

U

UU

polyu

biquit

ylatio

n

proteosomedegradation

HIF-α remains undegraded in hypoxia dimerizes and forms TF

Minutes exposed to 20 O2

H1F-

Hours exposed to 1 O2

Hypoxia

(inhibition of hydroxylases)

4

OHOH

Transc

riptio

n

Factor

VEGFPhosphoglycerate Kinase

Glut-1Erythropoietin

VHL-- mutants are embryonic lethal due to vasculature malformation

D melanogaster embryos

WT

ds d

-VH

L R

NA

5 Mice embryos Day E105

WT

VH

L--

6

Heterozygousconditional VHL knockouts cause hemangiomas in mice

6

VHL1+ (heterozygous) mice Albumin-cre mutant mice liver cells

Kidney VHL knockouts in mice cause pre-cancerous phenotypes

7

Human VHL Disease is characterized by vascular tumors in many tissues

8

References1 Hsu T (2012) Complex cellular functions of the von HippelndashLindau 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 2156ndash2161

3 Min J Yang H Ivan M Gertler F Kaelin WG Pavletich NP (2007) Structure of an HIF-11113097ndashpVHL 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 O2 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 2803ndash2811

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 9102ndash9107

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

• pVHL and von Hippel-Lindau Disease
• paradigm
• questions
• pVHL is part of an E3 ubiquitin ligase complex
• pVHL binds and ubiquitylates HIF-α to target for degradation
• HIF-α remains undegraded in hypoxia dimerizes and forms TF
• VHL-- mutants are embryonic lethal due to vasculature malforma
• Heterozygousconditional VHL knockouts cause hemangiomas in mic
• Kidney VHL knockouts in mice cause pre-cancerous phenotypes
• Human VHL Disease is characterized by vascular tumors in many t
• References

pVHL is part of an E3 ubiquitin ligase complex

21

pVHL binds and ubiquitylates HIF-α to target for degradation

3

OH

OH

OH

OH

U

U

UU

polyu

biquit

ylatio

n

proteosomedegradation

HIF-α remains undegraded in hypoxia dimerizes and forms TF

Minutes exposed to 20 O2

H1F-

Hours exposed to 1 O2

Hypoxia

(inhibition of hydroxylases)

4

OHOH

Transc

riptio

n

Factor

VEGFPhosphoglycerate Kinase

Glut-1Erythropoietin

VHL-- mutants are embryonic lethal due to vasculature malformation

D melanogaster embryos

WT

ds d

-VH

L R

NA

5 Mice embryos Day E105

WT

VH

L--

6

Heterozygousconditional VHL knockouts cause hemangiomas in mice

6

VHL1+ (heterozygous) mice Albumin-cre mutant mice liver cells

Kidney VHL knockouts in mice cause pre-cancerous phenotypes

7

Human VHL Disease is characterized by vascular tumors in many tissues

8

References1 Hsu T (2012) Complex cellular functions of the von HippelndashLindau 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 2156ndash2161

3 Min J Yang H Ivan M Gertler F Kaelin WG Pavletich NP (2007) Structure of an HIF-11113097ndashpVHL 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 O2 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 2803ndash2811

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 9102ndash9107

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

• pVHL and von Hippel-Lindau Disease
• paradigm
• questions
• pVHL is part of an E3 ubiquitin ligase complex
• pVHL binds and ubiquitylates HIF-α to target for degradation
• HIF-α remains undegraded in hypoxia dimerizes and forms TF
• VHL-- mutants are embryonic lethal due to vasculature malforma
• Heterozygousconditional VHL knockouts cause hemangiomas in mic
• Kidney VHL knockouts in mice cause pre-cancerous phenotypes
• Human VHL Disease is characterized by vascular tumors in many t
• References

pVHL binds and ubiquitylates HIF-α to target for degradation

3

OH

OH

OH

OH

U

U

UU

polyu

biquit

ylatio

n

proteosomedegradation

HIF-α remains undegraded in hypoxia dimerizes and forms TF

Minutes exposed to 20 O2

H1F-

Hours exposed to 1 O2

Hypoxia

(inhibition of hydroxylases)

4

OHOH

Transc

riptio

n

Factor

VEGFPhosphoglycerate Kinase

Glut-1Erythropoietin

VHL-- mutants are embryonic lethal due to vasculature malformation

D melanogaster embryos

WT

ds d

-VH

L R

NA

5 Mice embryos Day E105

WT

VH

L--

6

Heterozygousconditional VHL knockouts cause hemangiomas in mice

6

VHL1+ (heterozygous) mice Albumin-cre mutant mice liver cells

Kidney VHL knockouts in mice cause pre-cancerous phenotypes

7

Human VHL Disease is characterized by vascular tumors in many tissues

8

References1 Hsu T (2012) Complex cellular functions of the von HippelndashLindau 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 2156ndash2161

3 Min J Yang H Ivan M Gertler F Kaelin WG Pavletich NP (2007) Structure of an HIF-11113097ndashpVHL 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 O2 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 2803ndash2811

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 9102ndash9107

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

• pVHL and von Hippel-Lindau Disease
• paradigm
• questions
• pVHL is part of an E3 ubiquitin ligase complex
• pVHL binds and ubiquitylates HIF-α to target for degradation
• HIF-α remains undegraded in hypoxia dimerizes and forms TF
• VHL-- mutants are embryonic lethal due to vasculature malforma
• Heterozygousconditional VHL knockouts cause hemangiomas in mic
• Kidney VHL knockouts in mice cause pre-cancerous phenotypes
• Human VHL Disease is characterized by vascular tumors in many t
• References

HIF-α remains undegraded in hypoxia dimerizes and forms TF

Minutes exposed to 20 O2

H1F-

Hours exposed to 1 O2

Hypoxia

(inhibition of hydroxylases)

4

OHOH

Transc

riptio

n

Factor

VEGFPhosphoglycerate Kinase

Glut-1Erythropoietin

VHL-- mutants are embryonic lethal due to vasculature malformation

D melanogaster embryos

WT

ds d

-VH

L R

NA

5 Mice embryos Day E105

WT

VH

L--

6

Heterozygousconditional VHL knockouts cause hemangiomas in mice

6

VHL1+ (heterozygous) mice Albumin-cre mutant mice liver cells

Kidney VHL knockouts in mice cause pre-cancerous phenotypes

7

Human VHL Disease is characterized by vascular tumors in many tissues

8

References1 Hsu T (2012) Complex cellular functions of the von HippelndashLindau 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 2156ndash2161

3 Min J Yang H Ivan M Gertler F Kaelin WG Pavletich NP (2007) Structure of an HIF-11113097ndashpVHL 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 O2 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 2803ndash2811

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 9102ndash9107

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

• pVHL and von Hippel-Lindau Disease
• paradigm
• questions
• pVHL is part of an E3 ubiquitin ligase complex
• pVHL binds and ubiquitylates HIF-α to target for degradation
• HIF-α remains undegraded in hypoxia dimerizes and forms TF
• VHL-- mutants are embryonic lethal due to vasculature malforma
• Heterozygousconditional VHL knockouts cause hemangiomas in mic
• Kidney VHL knockouts in mice cause pre-cancerous phenotypes
• Human VHL Disease is characterized by vascular tumors in many t
• References

VHL-- mutants are embryonic lethal due to vasculature malformation

D melanogaster embryos

WT

ds d

-VH

L R

NA

5 Mice embryos Day E105

WT

VH

L--

6

Heterozygousconditional VHL knockouts cause hemangiomas in mice

6

VHL1+ (heterozygous) mice Albumin-cre mutant mice liver cells

Kidney VHL knockouts in mice cause pre-cancerous phenotypes

7

Human VHL Disease is characterized by vascular tumors in many tissues

8

References1 Hsu T (2012) Complex cellular functions of the von HippelndashLindau 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 2156ndash2161

3 Min J Yang H Ivan M Gertler F Kaelin WG Pavletich NP (2007) Structure of an HIF-11113097ndashpVHL 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 O2 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 2803ndash2811

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 9102ndash9107

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

• pVHL and von Hippel-Lindau Disease
• paradigm
• questions
• pVHL is part of an E3 ubiquitin ligase complex
• pVHL binds and ubiquitylates HIF-α to target for degradation
• HIF-α remains undegraded in hypoxia dimerizes and forms TF
• VHL-- mutants are embryonic lethal due to vasculature malforma
• Heterozygousconditional VHL knockouts cause hemangiomas in mic
• Kidney VHL knockouts in mice cause pre-cancerous phenotypes
• Human VHL Disease is characterized by vascular tumors in many t
• References

Heterozygousconditional VHL knockouts cause hemangiomas in mice

6

VHL1+ (heterozygous) mice Albumin-cre mutant mice liver cells

Kidney VHL knockouts in mice cause pre-cancerous phenotypes

7

Human VHL Disease is characterized by vascular tumors in many tissues

8

References1 Hsu T (2012) Complex cellular functions of the von HippelndashLindau 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 2156ndash2161

3 Min J Yang H Ivan M Gertler F Kaelin WG Pavletich NP (2007) Structure of an HIF-11113097ndashpVHL 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 O2 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 2803ndash2811

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 9102ndash9107

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

• pVHL and von Hippel-Lindau Disease
• paradigm
• questions
• pVHL is part of an E3 ubiquitin ligase complex
• pVHL binds and ubiquitylates HIF-α to target for degradation
• HIF-α remains undegraded in hypoxia dimerizes and forms TF
• VHL-- mutants are embryonic lethal due to vasculature malforma
• Heterozygousconditional VHL knockouts cause hemangiomas in mic
• Kidney VHL knockouts in mice cause pre-cancerous phenotypes
• Human VHL Disease is characterized by vascular tumors in many t
• References

Kidney VHL knockouts in mice cause pre-cancerous phenotypes

7

Human VHL Disease is characterized by vascular tumors in many tissues

8

References1 Hsu T (2012) Complex cellular functions of the von HippelndashLindau 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 2156ndash2161

3 Min J Yang H Ivan M Gertler F Kaelin WG Pavletich NP (2007) Structure of an HIF-11113097ndashpVHL 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 O2 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 2803ndash2811

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 9102ndash9107

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

• pVHL and von Hippel-Lindau Disease
• paradigm
• questions
• pVHL is part of an E3 ubiquitin ligase complex
• pVHL binds and ubiquitylates HIF-α to target for degradation
• HIF-α remains undegraded in hypoxia dimerizes and forms TF
• VHL-- mutants are embryonic lethal due to vasculature malforma
• Heterozygousconditional VHL knockouts cause hemangiomas in mic
• Kidney VHL knockouts in mice cause pre-cancerous phenotypes
• Human VHL Disease is characterized by vascular tumors in many t
• References

Human VHL Disease is characterized by vascular tumors in many tissues

8

References1 Hsu T (2012) Complex cellular functions of the von HippelndashLindau 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 2156ndash2161

3 Min J Yang H Ivan M Gertler F Kaelin WG Pavletich NP (2007) Structure of an HIF-11113097ndashpVHL 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 O2 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 2803ndash2811

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 9102ndash9107

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

• pVHL and von Hippel-Lindau Disease
• paradigm
• questions
• pVHL is part of an E3 ubiquitin ligase complex
• pVHL binds and ubiquitylates HIF-α to target for degradation
• HIF-α remains undegraded in hypoxia dimerizes and forms TF
• VHL-- mutants are embryonic lethal due to vasculature malforma
• Heterozygousconditional VHL knockouts cause hemangiomas in mic
• Kidney VHL knockouts in mice cause pre-cancerous phenotypes
• Human VHL Disease is characterized by vascular tumors in many t
• References

References1 Hsu T (2012) Complex cellular functions of the von HippelndashLindau 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 2156ndash2161

3 Min J Yang H Ivan M Gertler F Kaelin WG Pavletich NP (2007) Structure of an HIF-11113097ndashpVHL 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 O2 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 2803ndash2811

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 9102ndash9107

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

• pVHL and von Hippel-Lindau Disease
• paradigm
• questions
• pVHL is part of an E3 ubiquitin ligase complex
• pVHL binds and ubiquitylates HIF-α to target for degradation
• HIF-α remains undegraded in hypoxia dimerizes and forms TF
• VHL-- mutants are embryonic lethal due to vasculature malforma
• Heterozygousconditional VHL knockouts cause hemangiomas in mic
• Kidney VHL knockouts in mice cause pre-cancerous phenotypes
• Human VHL Disease is characterized by vascular tumors in many t
• References