William Kaelin

Summary

Affiliation: Harvard University
Country: USA

Publications

  1. pmc HIF hydroxylation and the mammalian oxygen-sensing pathway
    Michal Safran
    Howard Hughes Medical Institute, Dana Farber Cancer Institute and Brigham and Women s Hospital, Boston, Massachusetts 02115, USA
    J Clin Invest 111:779-83. 2003
  2. ncbi request reprint The concept of synthetic lethality in the context of anticancer therapy
    William G Kaelin
    Howard Hughes Medical Institute, 44 Binney Street, Mayer 457, Boston, Massachusetts 02115, USA
    Nat Rev Cancer 5:689-98. 2005
  3. 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
  4. pmc Treatment of erythropoietin deficiency in mice with systemically administered siRNA
    William Querbes
    Alnylam Pharmaceuticals, Cambridge, MA 02215, USA
    Blood 120:1916-22. 2012
  5. doi request reprint Cancer and altered metabolism: potential importance of hypoxia-inducible factor and 2-oxoglutarate-dependent dioxygenases
    W G Kaelin
    Howard Hughes Medical Institute, Dana Farber Cancer Institute and Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA
    Cold Spring Harb Symp Quant Biol 76:335-45. 2011
  6. doi request reprint Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway
    William G Kaelin
    Howard Hughes Medical Institute, Boston, MA 02115, USA
    Mol Cell 30:393-402. 2008
  7. ncbi request reprint Von Hippel-Lindau disease
    William G Kaelin
    Department of Medical Oncology, Dana Farber Cancer Institute and Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
    Annu Rev Pathol 2:145-73. 2007
  8. ncbi request reprint The von Hippel-Lindau tumor suppressor protein and clear cell renal carcinoma
    William G Kaelin
    Howard Hughes Medical Institute, Dana Farber Cancer Institute and Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    Clin Cancer Res 13:680s-684s. 2007
  9. ncbi request reprint The von Hippel-Lindau protein, HIF hydroxylation, and oxygen sensing
    William G Kaelin
    Howard Hughes Medical Institute, Dana Farber Cancer Institute and Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    Biochem Biophys Res Commun 338:627-38. 2005
  10. ncbi request reprint Alterations in G1/S cell-cycle control contributing to carcinogenesis
    W G Kaelin
    Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA
    Ann N Y Acad Sci 833:29-33. 1997

Detail Information

Publications82

  1. pmc HIF hydroxylation and the mammalian oxygen-sensing pathway
    Michal Safran
    Howard Hughes Medical Institute, Dana Farber Cancer Institute and Brigham and Women s Hospital, Boston, Massachusetts 02115, USA
    J Clin Invest 111:779-83. 2003
  2. ncbi request reprint The concept of synthetic lethality in the context of anticancer therapy
    William G Kaelin
    Howard Hughes Medical Institute, 44 Binney Street, Mayer 457, Boston, Massachusetts 02115, USA
    Nat Rev Cancer 5:689-98. 2005
    ..This is changing as a result of the increased availability of chemical and genetic tools for perturbing gene function in somatic cells...
  3. 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...
  4. pmc Treatment of erythropoietin deficiency in mice with systemically administered siRNA
    William Querbes
    Alnylam Pharmaceuticals, Cambridge, MA 02215, USA
    Blood 120:1916-22. 2012
    ....
  5. doi request reprint Cancer and altered metabolism: potential importance of hypoxia-inducible factor and 2-oxoglutarate-dependent dioxygenases
    W G Kaelin
    Howard Hughes Medical Institute, Dana Farber Cancer Institute and Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA
    Cold Spring Harb Symp Quant Biol 76:335-45. 2011
    ..2-Oxoglutarate-dependent dioxygenases therefore provide a link between altered metabolism and cancer...
  6. doi request reprint Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway
    William G Kaelin
    Howard Hughes Medical Institute, Boston, MA 02115, USA
    Mol Cell 30:393-402. 2008
    ..HIF affects signaling pathways that influence development, metabolism, inflammation, and integrative physiology. Accordingly, HIF-modulatory drugs are now being developed for diverse diseases...
  7. ncbi request reprint Von Hippel-Lindau disease
    William G Kaelin
    Department of Medical Oncology, Dana Farber Cancer Institute and Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
    Annu Rev Pathol 2:145-73. 2007
    ..It is hypothesized that tumor-associated alleles of these genes allow primitive sympathoadrenal precursors to escape developmental culling, and that such cells are at increased risk of forming tumors...
  8. ncbi request reprint The von Hippel-Lindau tumor suppressor protein and clear cell renal carcinoma
    William G Kaelin
    Howard Hughes Medical Institute, Dana Farber Cancer Institute and Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    Clin Cancer Res 13:680s-684s. 2007
    ....
  9. ncbi request reprint The von Hippel-Lindau protein, HIF hydroxylation, and oxygen sensing
    William G Kaelin
    Howard Hughes Medical Institute, Dana Farber Cancer Institute and Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    Biochem Biophys Res Commun 338:627-38. 2005
    ..Pharmacological manipulation of HIF activity might be beneficial in diseases characterized by abnormal tissue oxygenation including myocardial infarction, cerebrovascular disease, and cancer...
  10. ncbi request reprint Alterations in G1/S cell-cycle control contributing to carcinogenesis
    W G Kaelin
    Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA
    Ann N Y Acad Sci 833:29-33. 1997
    ..Thus, E2F appears to be a physiologically relevant target of pRB action, and deregulation of E2F-responsive genes is a common, and possibly universal, step in human carcinogenesis...
  11. ncbi request reprint E2F1 as a target: promoter-driven suicide and small molecule modulators
    William G Kaelin
    Dana Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA
    Cancer Biol Ther 2:S48-54. 2003
    ..This chapter will review the role of E2F in cancer and outline opportunities for the development of anticancer agents based on E2F biology...
  12. ncbi request reprint The von Hippel-Lindau gene, kidney cancer, and oxygen sensing
    William G Kaelin
    Howard Hughes Medical Institute, Dana Farber Cancer Institute, and Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
    J Am Soc Nephrol 14:2703-11. 2003
    ..This review summarizes the current knowledge of the molecular pathogenesis of von Hippel-Lindau disease and the role of the VHL gene product (pVHL) in kidney cancer and the mammalian oxygen sensing pathway...
  13. ncbi request reprint Proline hydroxylation and gene expression
    William G Kaelin
    Howard Hughes Medical Institute, Dana Farber Cancer Institute, Brigham and Women s Hospital, and Harvard Medical School, Boston, Massachusetts 02115, USA
    Annu Rev Biochem 74:115-28. 2005
    ..The existence of three human EGLN family members, as well as other putative hydroxylases, raises the possibility that this signal is used in other contexts by other proteins...
  14. ncbi request reprint The von Hippel-Lindau tumor suppressor gene and kidney cancer
    William G Kaelin
    Howard Hughes Medical Institute, Dana Farber Cancer Institute and Brigham and Women s Hospital, Boston, Massachusetts 02115, USA
    Clin Cancer Res 10:6290S-5S. 2004
    ..Genotype-phenotype correlations in VHL disease suggest, however, that pVHL has targets in addition to HIF. Elucidating these targets should provide a more complete picture of how pVHL suppresses tumor growth...
  15. doi request reprint The von Hippel-Lindau tumour suppressor protein: O2 sensing and cancer
    William G Kaelin
    Howard Hughes Medical Institute, Chevy Chase, Maryland 20815 6789, USA
    Nat Rev Cancer 8:865-73. 2008
    ....
  16. ncbi request reprint Molecular basis of the VHL hereditary cancer syndrome
    William G Kaelin
    Howard Hughes Medical Institute, Dana Farber Cancer Institute and Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
    Nat Rev Cancer 2:673-82. 2002
    ..These studies, in turn, are laying the foundation for the treatment of a diverse set of disorders, including cancer, myocardial infarction and stroke...
  17. ncbi request reprint Functions of the von Hippel-Lindau tumour suppressor protein
    W G Kaelin
    Dana Farber Cancer Institute and Brigham and Women s Hospital, Boston, MA 02115, USA
    J Intern Med 243:535-9. 1998
    ..In this regard, it is perhaps noteworthy that elongin C and Cul2 are homologous to yeast proteins Skp1 and Cdc53. These latter proteins participate in the formation of complexes that target certain proteins for ubiquitination...
  18. ncbi request reprint The emerging p53 gene family
    W G Kaelin
    Howard Hughes Medical Institute and Dana Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA
    J Natl Cancer Inst 91:594-8. 1999
    ..Additional studies are required to determine the role, if any, that p73 and p51 play in cell growth control and carcinogenesis...
  19. ncbi request reprint Functions of the retinoblastoma protein
    W G Kaelin
    Department of Adult Oncology and Howard Hughes Medical Institute, Dana Farber Cancer Institute, and Harvard Medical School, Boston, Massachusetts, USA
    Bioessays 21:950-8. 1999
    ..The untimely activation of E2F responsive genes can induce apoptosis. This comes about at least partly through the induction of ARF, which leads to the stabilization and activation of p53. BioEssays 1999;21:950-958...
  20. ncbi request reprint The p53 gene family
    W G Kaelin
    Howard Hughes Medical Institute and Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, MA 02115, USA
    Oncogene 18:7701-5. 1999
    ....
  21. doi request reprint New cancer targets emerging from studies of the Von Hippel-Lindau tumor suppressor protein
    William G Kaelin
    Howard Hughes Medical Institute, Dana Farber Cancer Institute and Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
    Ann N Y Acad Sci 1210:1-7. 2010
    ..A number of JmjC-containing proteins, including RBP2 and PLU-1, are 2-oxoglutarate-dependent dioxygenases that demethylate histones. Preclinical data suggest that inhibition of RBP2 or PLU-1 would suppress tumor growth...
  22. pmc Synthetic lethality: a framework for the development of wiser cancer therapeutics
    William G Kaelin
    Howard Hughes Medical Institute, Dana Farber Cancer Institute and Brigham and Women s Hospital, 44 Binney St, Boston, MA 02115, USA
    Genome Med 1:99. 2009
    ..These approaches will hopefully facilitate the discovery of safer, more efficacious anticancer drugs that exploit vulnerabilities that are unique to cancer cells by virtue of the mutations they have accrued during tumor progression...
  23. ncbi request reprint How oxygen makes its presence felt
    William G Kaelin
    Howard Hughes Medical Institute, Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA
    Genes Dev 16:1441-5. 2002
  24. doi request reprint 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...
  25. doi request reprint Treatment of kidney cancer: insights provided by the VHL tumor-suppressor protein
    William G Kaelin
    Howard Hughes Medical Institute, Dana Farber Cancer Institute and Brigham and Women s Hospital, Harvard Medical School, 44 Binney Street, Mayer 457, Boston, MA 02115, USA
    Cancer 115:2262-72. 2009
    ..Loss of the primary cilium probably facilitates the development of preneoplastic renal cysts, whereas increased NFkappaB might contribute to the resistance of kidney cancers to conventional cytotoxic agents...
  26. doi request reprint Kidney cancer: now available in a new flavor
    William G Kaelin
    Department of Medical Oncology, Dana Farber Cancer Institute, Brigham and Women s Hospital, and Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA
    Cancer Cell 14:423-4. 2008
    ..In this issue, Simon and coworkers show that the molecular signature of VHL(-/-) kidney cancers is profoundly influenced by whether they produce both HIF2alpha and HIF1alpha or HIF2alpha alone...
  27. ncbi request reprint Role of VHL gene mutation in human cancer
    William Y Kim
    Dana Farber Cancer Institute and Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    J Clin Oncol 22:4991-5004. 2004
    ..On the other hand, clear genotype-phenotype correlations are emerging in VHL disease and can be rationalized if pVHL has functions separate from its control of HIF...
  28. ncbi request reprint The von Hippel-Lindau tumor suppressor protein: new insights into oxygen sensing and cancer
    William Kim
    Howard Hughes Medical Institute, Dana Farber Cancer Institute and Brigham and Women s Hospital, Boston, Massachusetts 02115, USA
    Curr Opin Genet Dev 13:55-60. 2003
    ....
  29. ncbi request reprint Neuronal apoptosis linked to EglN3 prolyl hydroxylase and familial pheochromocytoma genes: developmental culling and cancer
    Sungwoo Lee
    Department of Medical Oncology, Dana Farber Cancer Institute and Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
    Cancer Cell 8:155-67. 2005
    ..Moreover, EglN3 proapoptotic activity requires SDH activity because EglN3 is feedback inhibited by succinate. These studies suggest that failure of developmental apoptosis plays a role in pheochromocytoma pathogenesis...
  30. pmc Biochemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible factor
    Mircea Ivan
    Dana Farber Cancer Institute and Brigham and Women s Hospital, Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA
    Proc Natl Acad Sci U S A 99:13459-64. 2002
    ..A model compound of this series stabilized HIF in a variety of cells, leading to the increased production of its downstream target, vascular endothelial growth factor...
  31. ncbi request reprint Inhibition of HIF is necessary for tumor suppression by the von Hippel-Lindau protein
    Keiichi Kondo
    Department of Adult Oncology, Dana Farber Cancer Institute and Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    Cancer Cell 1:237-46. 2002
    ..These studies prove that HIF is a critical downstream target of pVHL and establish that activation of HIF target genes can promote tumorigenesis in vivo...
  32. ncbi request reprint VHL and kidney cancer
    Michael Ohh
    Dana Farber Cancer Institute, Boston, MA, USA
    Methods Mol Biol 222:167-83. 2003
  33. ncbi request reprint TSC2 regulates VEGF through mTOR-dependent and -independent pathways
    James B Brugarolas
    Dana Farber Cancer Institute and Brigham and Women s Hospital, Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA
    Cancer Cell 4:147-58. 2003
    ..This pathway may involve chromatin remodeling since the HDAC inhibitor Trichostatin A downregulates VEGF in TSC2(-/-) cells...
  34. ncbi request reprint The von Hippel-Lindau protein, vascular endothelial growth factor, and kidney cancer
    Daniel J George
    Dana Farber Cancer Institute, Boston, USA
    N Engl J Med 349:419-21. 2003
  35. pmc Inhibition of HIF2alpha is sufficient to suppress pVHL-defective tumor growth
    Keiichi Kondo
    Department of Adult Oncology, Dana Farber Cancer Institute and Brigham and Womens Hospital, Harvard Medical School, Boston, Massachusetts, USA
    PLoS Biol 1:E83. 2003
    ..These results establish that tumor suppression by pVHL is linked to regulation of HIF target genes...
  36. ncbi request reprint Senescence triggered by the loss of the VHL tumor suppressor
    Arthur P Young
    Department of Developmental and Stem Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215, USA
    Cell Cycle 7:1709-12. 2008
  37. pmc Patterns of gene expression and copy-number alterations in von-hippel lindau disease-associated and sporadic clear cell carcinoma of the kidney
    Rameen Beroukhim
    Departments of Medical Oncology, Harvard Medical School, Boston, Massachusetts, USA
    Cancer Res 69:4674-81. 2009
    ....
  38. ncbi request reprint ROS: really involved in oxygen sensing
    William G Kaelin
    Howard Hughes Medical Institute, Dana Farber Cancer Institute, Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
    Cell Metab 1:357-8. 2005
    ..2005) used genetic tools to establish that ROS produced by mitochondria are required for the normal induction of HIF (hypoxia-inducible factor), which is a master regulator of oxygen-sensitive gene expression, by low oxygen...
  39. pmc Innovations and challenges in renal cancer: summary statement from the Third Cambridge Conference
    Michael B Atkins
    Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
    Cancer 115:2247-51. 2009
    ..The conference format combined brief presentations with extended periods of discussion. The conclusions and recommendations are summarized in this paper and presented in more detail in the individual papers that follow...
  40. ncbi request reprint Chemosensitivity linked to p73 function
    Meredith S Irwin
    Dana Farber Cancer Institute and Brigham and Womens Hospital, Harvard Medical School, Boston, MA 02115, USA
    Cancer Cell 3:403-10. 2003
    ..Mutant p53 can inactivate p73 and downregulation of mutant p53 enhanced chemosensitivity. These findings indicate that p73 is a determinant of chemotherapeutic efficacy in humans...
  41. doi request reprint Prostate cancer: beta control your hormones
    Massimo Loda
    Dana Farber Cancer Institute, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    Cancer Cell 17:311-2. 2010
    ....
  42. ncbi request reprint Analysis of von Hippel-Lindau hereditary cancer syndrome: implications of oxygen sensing
    Haifeng Yang
    Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA
    Methods Enzymol 381:320-35. 2004
  43. pmc The kinesin KIF1Bbeta acts downstream from EglN3 to induce apoptosis and is a potential 1p36 tumor suppressor
    Susanne Schlisio
    Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA
    Genes Dev 22:884-93. 2008
    ....
  44. ncbi request reprint Innovations and challenges in renal cell carcinoma: summary statement from the Second Cambridge Conference
    Michael B Atkins
    Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, USA
    Clin Cancer Res 13:667s-670s. 2007
    ....
  45. pmc Clusterin is a secreted marker for a hypoxia-inducible factor-independent function of the von Hippel-Lindau tumor suppressor protein
    Eijiro Nakamura
    Department of Medical Oncology, Dana Farber Cancer Institute, 44 Binney St, Boston, MA 02115, USA
    Am J Pathol 168:574-84. 2006
    ..Therefore, clusterin is a secreted marker for a HIF-independent pVHL function that might be especially important in pheochromocytoma development...
  46. pmc Hypoxia-inducible factor linked to differential kidney cancer risk seen with type 2A and type 2B VHL mutations
    Lianjie Li
    Department of Medical Oncology, Dana Farber Cancer Institute and Brigham and Women s Hospital, Harvard Medical School, 44 Binney Street, Mayer 457, Boston, MA 02115, USA
    Mol Cell Biol 27:5381-92. 2007
    ..Therefore, quantitative differences with respect to HIF deregulation are sufficient to account for the differential risks of kidney cancer linked to VHL mutations...
  47. pmc Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex
    James Brugarolas
    Dana Farber Cancer Institute and Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    Genes Dev 18:2893-904. 2004
    ..Inhibition of mTOR function by hypoxia is likely to be important for tumor suppression as TSC2-deficient cells maintain abnormally high levels of cell proliferation under hypoxia...
  48. pmc FoxOs enforce a progression checkpoint to constrain mTORC1-activated renal tumorigenesis
    Boyi Gan
    Belfer Institute for Applied Cancer Science, Boston, MA 02115, USA
    Cancer Cell 18:472-84. 2010
    ....
  49. doi request reprint VHL loss actuates a HIF-independent senescence programme mediated by Rb and p400
    Arthur P Young
    Department of Medical Oncology, Dana Farber Cancer Institute and Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
    Nat Cell Biol 10:361-9. 2008
    ..Our results suggest that senescence induced by VHL inactivation is a tumour-suppressive mechanism that must be overcome to develop VHL-associated neoplasias...
  50. ncbi request reprint Dysregulation of HIF and VEGF is a unifying feature of the familial hamartoma syndromes
    James Brugarolas
    Dana Farber Cancer Institute and Harvard Medical School, Howard Hughes Medical Institute, 44 Binney Street, Mayer 457, Boston, Massachusetts 02115, USA
    Cancer Cell 6:7-10. 2004
    ..How mTOR dysregulation after inactivation of LKB1 or TSC1/2 contributes to hamartoma development is not known. However, hypoxia-inducible factor (HIF) and VEGF are regulated by mTOR and are likely to play a contributory role...
  51. pmc Somatic inactivation of the PHD2 prolyl hydroxylase causes polycythemia and congestive heart failure
    Yoji Andrew Minamishima
    Department of Medical Oncology, Brigham and Women s Hospital and Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
    Blood 111:3236-44. 2008
    ..The latter is likely the result of hyperviscosity syndrome and volume overload, although a direct effect of chronic, high-level HIF stimulation on cardiac myocytes cannot be excluded...
  52. 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...
  53. 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...
  54. pmc An intact NEDD8 pathway is required for Cullin-dependent ubiquitylation in mammalian cells
    Michael Ohh
    Department of Adult Oncology, Dana Farber Cancer Institute and Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    EMBO Rep 3:177-82. 2002
    ..Thus, neddylation regulates the activity of two specific subclasses of mammalian ubiquitin ligases...
  55. ncbi request reprint Using cancer genetics to guide the selection of anticancer drug targets
    Archana Reddy
    Howard Hughes Medical Institute, Dana Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA
    Curr Opin Pharmacol 2:366-73. 2002
    ....
  56. ncbi request reprint The retinoblastoma binding protein RBP2 is an H3K4 demethylase
    Robert J Klose
    Howard Hughes Medical Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
    Cell 128:889-900. 2007
    ..These studies provide mechanistic insights into transcriptional regulation by RBP2 and provide the first example of a mammalian enzyme capable of erasing trimethylated H3K4...
  57. ncbi request reprint The v-Jun point mutation allows c-Jun to escape GSK3-dependent recognition and destruction by the Fbw7 ubiquitin ligase
    Wenyi Wei
    Department of Medical Oncology, Dana Farber Cancer Institute and Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    Cancer Cell 8:25-33. 2005
    ..These findings explain the enhanced stability and oncogenicity of v-Jun relative to its cellular counterpart and reveal that GSK3 and Fbw7 coordinately regulate c-Jun and c-Myc...
  58. pmc Failure to prolyl hydroxylate hypoxia-inducible factor alpha phenocopies VHL inactivation in vivo
    William Y Kim
    Department of Medical Oncology, Dana Farber Cancer Institute and Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    EMBO J 25:4650-62. 2006
    ..Therefore, the pathological changes caused by pVHL inactivation in skin and liver are due largely to dysregulation of HIF target genes...
  59. ncbi request reprint Bioluminescent imaging of Cdk2 inhibition in vivo
    Guo Jun Zhang
    Department of Adult Oncology, Dana Farber Cancer Institute and Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
    Nat Med 10:643-8. 2004
    ..In theory, the approach described here could be used to develop bioluminescent reporters for any drug target that directly or indirectly affects the turnover of a ubiquitin ligase substrate...
  60. 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
    ....
  61. pmc A feedback loop involving the Phd3 prolyl hydroxylase tunes the mammalian hypoxic response in vivo
    Yoji Andrew Minamishima
    Department of Medical Oncology, Dana Farber Cancer Institute and Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    Mol Cell Biol 29:5729-41. 2009
    ....
  62. pmc Reactivation of hepatic EPO synthesis in mice after PHD loss
    Yoji Andrew Minamishima
    Howard Hughes Medical Institute, Dana Farber Cancer Institute and Brigham and Women s Hospital, Boston, MA 02115, USA
    Science 329:407. 2010
    ....
  63. pmc Mouse model for noninvasive imaging of HIF prolyl hydroxylase activity: assessment of an oral agent that stimulates erythropoietin production
    Michal Safran
    Department of Medical Oncology, Dana Farber Cancer Institute, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    Proc Natl Acad Sci U S A 103:105-10. 2006
    ....
  64. ncbi request reprint Rapid and durable recovery of visual function in a patient with von hippel-lindau syndrome after systemic therapy with vascular endothelial growth factor receptor inhibitor su5416
    Lloyd Paul Aiello
    Beetham Eye Institute, Joslin Diabetes Center, 1 Joslin Place, Boston, Massachusetts 02115, USA
    Ophthalmology 109:1745-51. 2002
    ....
  65. ncbi request reprint Nineteenth Annual Pezcoller Symposium: hypothesis-driven clinical investigation in cancer
    William G Kaelin
    Dana Farber Cancer Institute, Boston, Massachusetts, USA
    Cancer Res 67:11102-5. 2007
    ..A session was devoted to the identification of markers of drug effectiveness. Two sessions were focused on opportunities for developing new specific molecular target-oriented therapies...
  66. pmc The hypoxia-inducible factor 2alpha N-terminal and C-terminal transactivation domains cooperate to promote renal tumorigenesis in vivo
    Qin Yan
    Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
    Mol Cell Biol 27:2092-102. 2007
    ....
  67. ncbi request reprint Retinoblastoma protein and anaphase-promoting complex physically interact and functionally cooperate during cell-cycle exit
    Ulrich K Binné
    Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts, MA 02129, USA
    Nat Cell Biol 9:225-32. 2007
    ..The results reveal an unexpected physical convergence between the pRB tumour-suppressor protein and E3 ligase complexes, and raise the possibility that pRB may direct APC/C to additional targets during pRB-mediated cell-cycle exit...
  68. ncbi request reprint Innovations and challenges in renal cancer: consensus statement from the first international conference
    Michael B Atkins
    Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA
    Clin Cancer Res 10:6277S-81S. 2004
  69. pmc The human p73 promoter: characterization and identification of functional E2F binding sites
    Ratnam S Seelan
    Department of Laboratory Medicine and Pathology, Division of Experimental Pathology, Mayo Clinic and Mayo Medical School, 200 First Street SW, Rochester, MN 55905, USA
    Neoplasia 4:195-203. 2002
    ..Two of the three functional E2F sites (at -155 and -132) reside within this region. Our results suggest that regulation of p73 expression is primarily mediated through binding of E2F1 to target sites at -155 and -132...
  70. ncbi request reprint Structure of an HIF-1alpha -pVHL complex: hydroxyproline recognition in signaling
    Jung Hyun Min
    Cellular Biochemistry and Biophysics Program and Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA
    Science 296:1886-9. 2002
    ..Although the beta sheet-like interactions contribute to the stability of the complex, the hydroxyproline contacts are central to the strict specificity characteristic of signaling...
  71. pmc pVHL modification by NEDD8 is required for fibronectin matrix assembly and suppression of tumor development
    Natalie H Stickle
    Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada
    Mol Cell Biol 24:3251-61. 2004
    ..These results suggest that NEDD8 modification of pVHL plays an important role in fibronectin matrix assembly and that in the absence of such regulation, an intact HIF pathway is insufficient to prevent VHL-associated tumorigenesis...
  72. pmc Diverse effects of mutations in exon II of the von Hippel-Lindau (VHL) tumor suppressor gene on the interaction of pVHL with the cytosolic chaperonin and pVHL-dependent ubiquitin ligase activity
    William J Hansen
    Surgical Research Laboratory, San Francisco General Hospital, 1001 Potrero Ave, San Francisco, CA 94110, USA
    Mol Cell Biol 22:1947-60. 2002
    ....
  73. ncbi request reprint Molecular pathways in renal cell carcinoma--rationale for targeted treatment
    William Y Kim
    Department of Hematology Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
    Semin Oncol 33:588-95. 2006
    ..How these agents should be combined with one another and with conventional agents is the subject of current trials...
  74. ncbi request reprint Gene expression profiling in a renal cell carcinoma cell line: dissecting VHL and hypoxia-dependent pathways
    Yide Jiang
    Genzyme Molecular Oncology, Framingham, MA 01701, USA
    Mol Cancer Res 1:453-62. 2003
    ....
  75. pmc Inhibition of vascular endothelial growth factor with a sequence-specific hypoxia response element antagonist
    Bogdan Z Olenyuk
    Division of Chemistry and Chemical Engineering, Beckman Institute, California Institute of Technology, Pasadena, CA 91125, USA
    Proc Natl Acad Sci U S A 101:16768-73. 2004
    ..Pathway-based regulation of hypoxia-inducible gene expression with DNA-binding small molecules may represent a new approach for targeting angiogenesis...
  76. ncbi request reprint Cell biology: divining cancer cell weaknesses
    William G Kaelin
    Nature 441:32-4. 2006
  77. ncbi request reprint The von hippel-lindau tumor suppressor protein: an update
    William G Kaelin
    Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, USA
    Methods Enzymol 435:371-83. 2007
    ..In addition, recent work suggests that pVHL regulates neuronal apoptosis in an HIF-independent manner, and this activity is linked to the risk of developing pheochromocytoma...
  78. ncbi request reprint Binding of pRB to the PHD protein RBP2 promotes cellular differentiation
    Elizaveta V Benevolenskaya
    Dana Farber Cancer Institute and Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
    Mol Cell 18:623-35. 2005
    ..Our results suggest that promotion of differentiation by pRB involves neutralization of free RBP2 and transcriptional activation of RBP2 targets linked to euchromatin maintenance...
  79. ncbi request reprint Recent insights into the molecular pathogenesis of pheochromocytoma and paraganglioma
    Eijiro Nakamura
    Department of Urology, Graduate School of Medicine, Kyoto University
    Endocr Pathol 17:97-106. 2006
    ..This review focuses on the genetics of these tumors and suggests a possible link between familial pheochromocytomas/paraganglioma genes and control of neuronal apoptosis during embryological development...
  80. ncbi request reprint Gleevec: prototype or outlier?
    William G Kaelin
    Howard Hughes Medical Institute, Dana Farber Cancer Institute and Brigham and Women s Hospital, Boston, MA 02115, USA
    Sci STKE 2004:pe12. 2004
    ..Encouraging in this regard are cell culture experiments and animal models that suggest that cancer cells often remain dependent on, and may become addicted to, the signals resulting from such early genetic changes...
  81. pmc Detection of peptides, proteins, and drugs that selectively interact with protein targets
    Ilya G Serebriiskii
    Division of Basic Science, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA
    Genome Res 12:1785-91. 2002
    ....
  82. ncbi request reprint Bioluminescent imaging of ubiquitin ligase activity: measuring Cdk2 activity in vivo through changes in p27 turnover
    Guo Jun Zhang
    Howard Hughes Medical Institute, Dana Farber Cancer Institute and Brighan and Women s Hospital, Harvard Medical School, Boston, Massachusetts, USA
    Methods Enzymol 399:530-49. 2005
    ..These approaches should be generalizable to other ubiquitin-ligase substrate pairs...

Research Grants31

  1. Real-Time Imaging of Hypoxia based on VHL Activity
    William Kaelin; Fiscal Year: 2006
    ..Such mice could be used to study diseases characterized by the presence of hypoxic cells, such as cancer, and could also be used to monitor pharmacodynamic effects of agents that alter tissue oxygenation and/or modulate HIF. ..
  2. 2006 Cancer Model Mechanisms
    William Kaelin; Fiscal Year: 2006
    ....
  3. A Luciferase Fusion Protein Library to Identify & Monitor Ubiquitylation Targets
    William Kaelin; Fiscal Year: 2007
    ..Reisolation of HIF in aims 2 and 3 would constitute proof of concept with respect to the potential utility of this approach. ..
  4. SIGNAL TRANSDUCTION BY THE RETINOBLASTOMA PROTEIN
    William Kaelin; Fiscal Year: 2007
    ..The functional significance of pRB/RBP2 interactions will be addressed in Specific aim 3 and specific aim 4 will ask whether EID1 and/or RBP2 contribute to the developmental abnormalities observed in RB-/- mice. ..
  5. Functional Analysis of the Von Hippel-Lindau Protein
    William Kaelin; Fiscal Year: 2007
    ..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. ..
  6. Functional Analysis of the Von Hippel-Lindau Protein
    William Kaelin; Fiscal Year: 2009
    ..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. ..
  7. Functional Analysis of the Von Hippel-Lindau Protein
    William G Kaelin; Fiscal Year: 2010
    ..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. ..
  8. Functional Analysis of the von Hippel Lindau Protein
    William Kaelin; Fiscal Year: 2005
    ..Identification of additional proteins that bind to, and are regulated by, pVHL is the goal of specific aim 4. ..
  9. Using Synthetic Lethality to Select Cancer Drug Targets
    William Kaelin; Fiscal Year: 2005
    ..Moreover, they may establish a new paradigm for the selection of anticancer drug targets based on inactivating mutations of TSG. ..
  10. FUNCTIONAL ANALYSIS OF THE VON HIPPEL/LINDAU PROTEIN
    William Kaelin; Fiscal Year: 2000
    ..Furthermore, these cDNAs will likely be invaluable reagents for further exploring the functional significance of pVHL binding to these two proteins. ..
  11. SIGNAL TRANSDUCTION BY THE RETINOBLASTOMA PROTEIN
    William Kaelin; Fiscal Year: 2002
    ..Testing this hypothesis in a mouse model, as well as determining the biochemical basis for this activity, will form the basis of specific aim 2. ..
  12. Functional Analysis of the Von Hippel-Lindau Protein
    William Kaelin; Fiscal Year: 2009
    ..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. ..