Functional Analysis of the Von Hippel-Lindau Protein

Summary

Principal Investigator: William Kaelin
Affiliation: Harvard University
Country: USA
Abstract: Von Hippel-Lindau disease is a hereditary cancer syndrome characterized by an increased risk of central nervous system tumors (hemangioblastomas), kidney cancer, and adrenal gland tumors (pheochromocytomas). This disorder arises in individuals who harbor a defective copy of the VHL tumor suppressor gene. VHL inactivation is also common in non-hereditary kidney cancers and hemangioblastomas. The best understood function of the VHL gene product (pVHL) relates to 'HIF', which is a master transcriptional regulator of genes involved in adaptation to hypoxia. HIF consists of two proteins, an 'alpha'subunit and a 'beta'subunit. pVHL targets HIFalpha for destruction when oxygen is present. The physical interaction of pVHL with HIFalpha requires that HIFalpha be hydroxylated on one of two prolyl residues by EglN1, which is an oxygen-dependent enzyme. pVHL-defective cells fail to destroy HIFalpha and consequently overexpress various HIF-responsive genes. There are 3 HIFalpha family members although HIF2alpha appears to be most relevant with respect to kidney cancer. Specific aim 1 will ask whether HIFalpha (especially HIF2alpha) stabilization in the mouse is sufficient to cause the pathological changes observed when pVHL is defective. Some VHL mutations cause very different risks of kidney cancer despite sharing HIFalpha defects. Specific aim 2 will attempt to understand the basis for this differential risk using cell biological, genomic, and biochemical approaches. Some VHL mutations preserve the ability to regulate HIF and yet cause pheochromocytoma. We recently found that all of the genes linked to familial pheochromocytoma (VHL, NF1, c-Ret, SDHB, SDHC, SDHD) regulate apoptosis of sympathoadrehal precursor cells following NGF withdrawal and that pheochromocytoma-associated alleles allow cells to escape cell death in this setting. Apoptosis after NGF withdrawal requires EglN3, a paralog of the HIF prolyl hydroxylase EglN1. Specific aim 3 will attempt to elucidate how EglN3 induces apoptosis. Many human cancers are driven by excessive Cyclin D1 activity. In the fly, elimination of the sole EglN family member impairs Cyclin D-dependent proliferation. In aim 4 we will pursue our preliminary data that loss of EglN2, the third member of the mammalian EglN family, downregulates Cyclin D1 in vitro and in vivo. This work is relevant to many human cancers and has already motivated successful clinical trials of agents that inhibit HIF-responsive growth factors (such as VEGF) in kidney cancer. Work in this area has also provided new insights into how human cells 'sense'and respond to inadequate oxygen availability. This, in turn, is leading to new drugs that might be useful in diseases such as heart attack and stroke that are characterized by impaired oxygen delivery to tissues.
Funding Period: ----------------1996 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc pVHL acts as an adaptor to promote the inhibitory phosphorylation of the NF-kappaB agonist Card9 by CK2
    Haifeng Yang
    Department of Medical Oncology, Dana Farber Cancer Institute and Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    Mol Cell 28:15-27. 2007
  2. pmc SQSTM1 is a pathogenic target of 5q copy number gains in kidney cancer
    Lianjie Li
    Department of Medical Oncology, Dana Farber Cancer Institute and Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    Cancer Cell 24:738-50. 2013
  3. pmc The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins
    Gang Lu
    Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02215, USA
    Science 343:305-9. 2014
  4. pmc Platelet-derived growth factor/vascular endothelial growth factor receptor inactivation by sunitinib results in Tsc1/Tsc2-dependent inhibition of TORC1
    Tram Anh Tran
    Department of Developmental Biology
    Mol Cell Biol 33:3762-79. 2013
  5. pmc What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer
    Julie Aurore Losman
    Department of Medical Oncology, Dana Farber Cancer Institute, Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA
    Genes Dev 27:836-52. 2013
  6. pmc Influence of metabolism on epigenetics and disease
    William G Kaelin
    Department of Medical Oncology, Dana Farber Cancer Institute and Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02215, USA
    Cell 153:56-69. 2013
  7. pmc (R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible
    Julie Aurore Losman
    Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02215, USA
    Science 339:1621-5. 2013
  8. pmc The VHL/HIF axis in clear cell renal carcinoma
    Chuan Shen
    Howard Hughes Medical Insititute, Dana Farber Cancer Institute and Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02215, United States
    Semin Cancer Biol 23:18-25. 2013
  9. pmc Treatment of erythropoietin deficiency in mice with systemically administered siRNA
    William Querbes
    Alnylam Pharmaceuticals, Cambridge, MA 02215, USA
    Blood 120:1916-22. 2012
  10. pmc Mutation analysis of HIF prolyl hydroxylases (PHD/EGLN) in individuals with features of phaeochromocytoma and renal cell carcinoma susceptibility
    Dewi Astuti
    Centre for Rare Diseases and Personalised Medicine, University of Birmingham, Birmingham B15 2TT, UK
    Endocr Relat Cancer 18:73-83. 2011

Scientific Experts

  • William Kaelin
  • Chuan Shen
  • Lianjie Li
  • Julie Aurore Losman
  • Javid Moslehi
  • David E Root
  • Sabina Signoretti
  • KWOK KIN WONG
  • Esra A Akbay
  • Gang Lu
  • Tram Anh Tran
  • Glenn S Cowley
  • Rameen Beroukhim
  • William Querbes
  • Lisa R Rogers
  • Dewi Astuti
  • Wenyi Wei
  • Benjamin L Ebert
  • Qing Zhang
  • Susanne Schlisio
  • Yoji Andrew Minamishima
  • Haifeng Yang
  • Keith L Ligon
  • Jaekyoung Son
  • Sudeshna Fisch
  • Nabeel Bardeesy
  • Julie A Losman
  • Marie Keenan
  • Robert Padera
  • Huahang Sun
  • Travis J Cohoon
  • John M Asara
  • Eiki Kikuchi
  • Andrew L Kung
  • Philip C Amrein
  • Sushma Gurumurthy
  • Illana Stanley
  • Camilla L Christensen
  • Supriya Saha
  • Kristen Jones
  • James E Bradner
  • Wei Liu
  • Christopher J Ott
  • Richard E Middleton
  • Omar Abdel-Wahab
  • Jeremy H Tchaicha
  • Sung Choe
  • Nika N Danial
  • Amir T Fathi
  • Camelia Gliser
  • MarkVic Naniong
  • Julian Carretero
  • Kelly M Stewart
  • Stuart Murray
  • Haikuo Zhang
  • Shakti H Ramkissoon
  • Kazumasa Uno
  • Alec C Kimmelman
  • Constantine S Mitsiades
  • Roderick T Bronson
  • Katharine E Yen
  • Patrick Lizotte
  • Christine McMahon
  • Samuel Peña-Llopis
  • Peppi Koivunen
  • Ryan E Looper
  • Eijiro Nakamura
  • Lisa Kinch
  • Pablo Tamayo
  • A Ari Hakimi
  • Lutz Kockel
  • Anders Jacobsen
  • Kiyohiro Ando
  • Barbara Tabak
  • Nikolaus Schultz
  • Chris Sander
  • James Brugarolas
  • Huaqi Jiang
  • Sungwoo Lee
  • James J Hsieh
  • Giovanni Ciriello
  • Rebekka K Schneider
  • Su Chun Cheng
  • Steven Bair
  • Nick Grishin
  • Ella Liberzon
  • Aviad Tsherniak
  • Akin Akinc
  • Satya Kuchimanchi
  • Kevin Fitzgerald

Detail Information

Publications19

  1. pmc pVHL acts as an adaptor to promote the inhibitory phosphorylation of the NF-kappaB agonist Card9 by CK2
    Haifeng Yang
    Department of Medical Oncology, Dana Farber Cancer Institute and Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    Mol Cell 28:15-27. 2007
    ..Therefore pVHL can serve as an adaptor for both a ubiquitin conjugating enzyme and a kinase. The latter activity, which promotes Card9 phosphorylation, links pVHL to control of NF-kappaB activity and tumorigenesis...
  2. pmc SQSTM1 is a pathogenic target of 5q copy number gains in kidney cancer
    Lianjie Li
    Department of Medical Oncology, Dana Farber Cancer Institute and Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    Cancer Cell 24:738-50. 2013
    ..Therefore, the selection pressure to amplify 5q in ccRCC is driven, at least partly, by SQSTM1. ..
  3. pmc The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins
    Gang Lu
    Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02215, USA
    Science 343:305-9. 2014
    ....
  4. pmc Platelet-derived growth factor/vascular endothelial growth factor receptor inactivation by sunitinib results in Tsc1/Tsc2-dependent inhibition of TORC1
    Tram Anh Tran
    Department of Developmental Biology
    Mol Cell Biol 33:3762-79. 2013
    ..Our findings provide insight into the mechanism of action of PVR and may have implications for understanding sunitinib sensitivity and resistance in tumors. ..
  5. pmc What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer
    Julie Aurore Losman
    Department of Medical Oncology, Dana Farber Cancer Institute, Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA
    Genes Dev 27:836-52. 2013
    ..Here we review what is known about the molecular mechanisms of transformation by mutant IDH and discuss their implications for the development of targeted therapies to treat IDH mutant malignancies...
  6. pmc Influence of metabolism on epigenetics and disease
    William G Kaelin
    Department of Medical Oncology, Dana Farber Cancer Institute and Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02215, USA
    Cell 153:56-69. 2013
    ..Here, we review literature pertinent to hypothetical connections between metabolic and epigenetic states in eukaryotic cells...
  7. pmc (R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible
    Julie Aurore Losman
    Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02215, USA
    Science 339:1621-5. 2013
    ..We provide evidence that this paradox relates to the ability of (S)-2HG, but not (R)-2HG, to inhibit the EglN prolyl hydroxylases. Additionally, we show that transformation by (R)-2HG is reversible...
  8. pmc The VHL/HIF axis in clear cell renal carcinoma
    Chuan Shen
    Howard Hughes Medical Insititute, Dana Farber Cancer Institute and Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02215, United States
    Semin Cancer Biol 23:18-25. 2013
    ..Indeed, clear cell renal carcinomas are exquisitely sensitive to VEGF deprivation and four VEGF inhibitors have now been approved for the treatment of this disease...
  9. pmc Treatment of erythropoietin deficiency in mice with systemically administered siRNA
    William Querbes
    Alnylam Pharmaceuticals, Cambridge, MA 02215, USA
    Blood 120:1916-22. 2012
    ....
  10. pmc Mutation analysis of HIF prolyl hydroxylases (PHD/EGLN) in individuals with features of phaeochromocytoma and renal cell carcinoma susceptibility
    Dewi Astuti
    Centre for Rare Diseases and Personalised Medicine, University of Birmingham, Birmingham B15 2TT, UK
    Endocr Relat Cancer 18:73-83. 2011
    ..No confirmed pathogenic mutations were detected suggesting that mutations in these genes are not a frequent cause of inherited phaeochromocytoma or RCC...
  11. pmc Erlotinib therapy for central nervous system hemangioblastomatosis associated with von Hippel-Lindau disease: a case report
    Lisa R Rogers
    Department of Neurology, Henry Ford Hospital, Detroit, MI, USA
    J Neurooncol 101:307-10. 2011
    ..The duration of response was 9 months. The median plasma and CSF levels of erlotinib while on treatment were 1146.06 and 247.83 ng/ml, respectively (CSF 21.6% of plasma). Erlotinib may have antitumor activity in CNS HBs...
  12. pmc D-2-hydroxyglutarate produced by mutant IDH2 causes cardiomyopathy and neurodegeneration in mice
    Esra A Akbay
    Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02215, USA
    Genes Dev 28:479-90. 2014
    ..Together, these findings indicate that inhibitors of mutant IDH2 may be beneficial in the treatment of D2HGA and suggest that 2HG produced by IDH mutant tumors has the potential to provoke a paraneoplastic condition. ..
  13. pmc Genetic and functional studies implicate HIF1α as a 14q kidney cancer suppressor gene
    Chuan Shen
    Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02215, USA
    Cancer Discov 1:222-35. 2011
    ..HIF1α activity is diminished in 14q-deleted kidney cancers, and all somatic HIF1α mutations identified in kidney cancers tested to date are loss of function. Therefore, HIF1α has the credentials of a kidney cancer suppressor gene...
  14. pmc New insights into the biology of renal cell carcinoma
    Lianjie Li
    Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, MD 20815, USA
    Hematol Oncol Clin North Am 25:667-86. 2011
    ..This review focuses primarily on the most common form of RCC, clear-cell renal carcinoma, noting some recent advances in the other histologic subtypes...
  15. pmc Good COP1 or bad COP1? In vivo veritas
    Wenyi Wei
    Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
    J Clin Invest 121:1263-5. 2011
    ..These findings challenge the view that COP1 regulates p53 stability and call into question the wisdom of developing COP1 inhibitors as potential anticancer agents...
  16. pmc Loss of hypoxia-inducible factor prolyl hydroxylase activity in cardiomyocytes phenocopies ischemic cardiomyopathy
    Javid Moslehi
    Department of Medical Oncology, Dana Farber Cancer Institute and Brigham and Women s Hospital, Harvard Medical School, 44 Binney St, Boston, MA 02115, USA
    Circulation 122:1004-16. 2010
    ....
  17. pmc Control of cyclin D1 and breast tumorigenesis by the EglN2 prolyl hydroxylase
    Qing Zhang
    Department of Medical Oncology, Dana Farber Cancer Institute and Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    Cancer Cell 16:413-24. 2009
    ..EglN2 depletion also impairs the fitness of lung, brain, and hematopoietic cancer lines. These findings support the exploration of EglN2 inhibitors as therapeutics for estrogen-dependent breast cancer and other malignancies...
  18. doi SDH5 mutations and familial paraganglioma: somewhere Warburg is smiling
    William G Kaelin
    Howard Hughes Medical Institute, Dana Farber Cancer Institute and Brigham and Women s Hospital, Boston, MA 02115, USA
    Cancer Cell 16:180-2. 2009
    ..Moreover, they detected SDH5 mutations in a large kindred with familial paraganglioma...