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William G. Kaelin Jr., MD


Researcher

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Researcher

  • Sidney Farber Professor of Medicine, Harvard Medical School
  • Investigator, Howard Hughes Medical Institute

Contact Information

  • Office Phone Number617-632-3975
  • Fax617-632-4760

Bio

William G. Kaelin, Jr., MD, is the 2019 Nobel Prize recipient in medicine or physiology. Dr. Kaelin received his MD from Duke University in 1982 and was a house officer and chief resident in internal medicine at Johns Hopkins Hospital. He was a medical oncology clinical fellow at Dana-Farber and a postdoctoral fellow in the laboratory of Dr. David Livingston, where he began his studies of tumor suppressor proteins. He became an independent investigator at Dana-Farber in 1992, and a Howard Hughes Medical Institute Investigator and Professor of Medicine at Harvard Medical School in 2002. The 2019 Nobel was awarded jointly to Kaelin, Sir Peter J. Ratcliffe and Gregg L. Semenza for their discoveries of how cells sense and adapt to oxygen availability.

Recent Awards:

  • Nobel Prize in Medicine or Physiology, 2019
  • Lasker Award for Basic Medical Research, Albert and Mary Lasker Foundation, 2016
  • Science of Oncology Award, ASCO 2016
  • The Princess Takamatsu Award, AACR 2016
  • Wiley Prize in Biomedical Sciences 2014
  • AACR Academy 2014
  • Steven C. Beering Award 2014
  • Scientific Grand Prix, Foundation Lefoulon-Delalande 2012
  • Stanley J. Korsmeyer Award, ASCI 2012
  • Alfred Knudson Award in Cancer Genetics, NCI 2011
  • Canada Gairdner International Award 2010
  • Elected to National Academy of Sciences 2010
  • AICR Colin Thomson Medal 2008
  • Elected to Institute of Medicine 2007
  • Duke University School of Medicine Distinguished Alumni Award 2007
  • Doris Duke Distinguished Clinical Investigator Award 2006
  • Richard and Hinda Rosenthal Foundation Award, AACR 2006
  • Elected to Johns Hopkins Society of Scholars 2003
  • Paul Marks Prize, Memorial Sloan Kettering Cancer Center 2001
  • James S. McDonnell Scholar Award 1993
  • NIH Physician-Scientist Award 1990
  • NIH National Research Service Award 1990
  • Alpha Omega Alpha Medical Honor Society 1983
  • Phi Beta Kappa 1978
  • Jill Rose Award 2020

Research

Functions of Tumor Suppressor Proteins

Our laboratory studies tumor suppressor genes and the normal functions of the proteins they encode. The long-term goal of this work is to lay the foundation for the development of new anticancer therapies based on the functions of specific tumor suppressor proteins. For example, it may be possible to develop a drug that mimics the behavior of a certain tumor suppressor protein, or to design strategies for killing only those cells in which a particular tumor suppressor protein has been inactivated, thus sparing normal cells.We are currently concentrating on the von Hippel-Lindau tumor suppressor protein (pVHL), the retinoblastoma tumor suppressor protein (pRB), and the p53-like protein p73. pVHL inactivation is common in several cancers including clear cell renal carcinoma. Our laboratory established that when oxygen is available, pVHL targets for destruction another protein called hypoxia-inducible factor (HIF). Cells lacking pVHL, or starved of oxygen, accumulate HIF, which activates a cadre of genes that facilitate adaptation to hypoxia. We showed that downregulation of HIF is both necessary and sufficient for pVHL to suppress the growth of renal carcinomas in experimental models. This work motivated clinical trials of agents that inhibit HIF-responsive growth factors such as vascular endothelial growth factor (VEGF). At least one VEGF inhibitor will likely be approved for the treatment of renal carcinoma in 2005.Earlier work by our group showed that the binding of pVHL to HIF requires that HIF be hydroxylated on one of two proline residues. Preclinical data suggest that preventing this modification pharmacologically might be useful for the treatment of diseases characterized by impaired oxygen delivery, including myocardial infarctions and strokes. In other research, we are studying tuberous sclerosis, a hereditary cancer syndrome caused by mutations of either the TSC1 or TSC2 genes. We recently discovered that TSC1 and TSC2, like pVHL, regulate HIF; we also found that another protein, REDD1, plays an important role in adaptation to chronic hypoxia by modulating the function of TSC1 and TSC2. The best understood function of the pRB protein is its ability to inhibit the E2F transcription factor. We discovered that pRB interacts with another protein, RBP2, which also has features of a transcription factor. Importantly, we showed that inhibition of RBP2 in cells lacking pRB induces some of the same changes observed following restoration of pRB function, including the induction of differentiation. We are now studying the biochemistry of RBP2 in greater detail.

Targeting oncoproteins with a positive selection assay for protein degraders. Sci Adv. 2021 Feb; 7(6).
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Author Correction: Skp2 dictates cell cycle-dependent metabolic oscillation between glycolysis and TCA cycle. Cell Res. 2021 Jan; 31(1):104.
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2-Oxoglutarate-dependent dioxygenases in cancer. Nat Rev Cancer. 2020 12; 20(12):710-726.
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Targeting the HIF2-VEGF axis in renal cell carcinoma. Nat Med. 2020 10; 26(10):1519-1530.
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Skp2 dictates cell cycle-dependent metabolic oscillation between glycolysis and TCA cycle. Cell Res. 2021 Jan; 31(1):80-93.
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CDK7 Inhibition Potentiates Genome Instability Triggering Anti-tumor Immunity in Small Cell Lung Cancer. Cancer Cell. 2020 01 13; 37(1):37-54.e9.
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Leveraging insights into cancer metabolism-a symposium report. Ann N Y Acad Sci. 2020 02; 1462(1):5-13.
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The KDM5A/RBP2 histone demethylase represses NOTCH signaling to sustain neuroendocrine differentiation and promote small cell lung cancer tumorigenesis. Genes Dev. 2019 12 01; 33(23-24):1718-1738.
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HIF-independent synthetic lethality between CDK4/6 inhibition and VHL loss across species. Sci Signal. 2019 10 01; 12(601).
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Mutant p53 induces a hypoxia transcriptional program in gastric and esophageal adenocarcinoma. JCI Insight. 2019 08 08; 4(15).
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EglN3 hydroxylase stabilizes BIM-EL linking VHL type 2C mutations to pheochromocytoma pathogenesis and chemotherapy resistance. Proc Natl Acad Sci U S A. 2019 08 20; 116(34):16997-17006.
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Histone demethylase KDM6A directly senses oxygen to control chromatin and cell fate. Science. 2019 03 15; 363(6432):1217-1222.
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Deubiquitinases Maintain Protein Homeostasis and Survival of Cancer Cells upon Glutathione Depletion. Cell Metab. 2019 05 07; 29(5):1166-1181.e6.
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Peptidic degron for IMiD-induced degradation of heterologous proteins. Proc Natl Acad Sci U S A. 2019 02 12; 116(7):2539-2544.
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Cells Lacking the RB1 Tumor Suppressor Gene Are Hyperdependent on Aurora B Kinase for Survival. Cancer Discov. 2019 02; 9(2):230-247.
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BRCA1-IRIS promotes human tumor progression through PTEN blockade and HIF-1a activation. Proc Natl Acad Sci U S A. 2018 10 09; 115(41):E9600-E9609.
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Transaminase Inhibition by 2-Hydroxyglutarate Impairs Glutamate Biosynthesis and Redox Homeostasis in Glioma. Cell. 2018 09 20; 175(1):101-116.e25.
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VHL substrate transcription factor ZHX2 as an oncogenic driver in clear cell renal cell carcinoma. Science. 2018 07 20; 361(6399):290-295.
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Autochthonous tumors driven by Rb1 loss have an ongoing requirement for the RBP2 histone demethylase. Proc Natl Acad Sci U S A. 2018 04 17; 115(16):E3741-E3748.
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HIF2 Inhibitor Joins the Kidney Cancer Armamentarium. J Clin Oncol. 2018 03 20; 36(9):908-910.
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Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma. Science. 2018 Feb 16; 359(6377):801-806.
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Senator McCain and Our Shared Humanity. Am J Med. 2018 03; 131(3):216-217.
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Climate Change: What Would Lincoln Do? JAMA. 2017 Aug 15; 318(7):611.
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HIF activation causes synthetic lethality between the VHL tumor suppressor and the EZH1 histone methyltransferase. Sci Transl Med. 2017 07 12; 9(398).
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The EGLN-HIF O2-Sensing System: Multiple Inputs and Feedbacks. Mol Cell. 2017 Jun 15; 66(6):772-779.
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Publish houses of brick, not mansions of straw. Nature. 2017 05 23; 545(7655):387.
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Common pitfalls in preclinical cancer target validation. Nat Rev Cancer. 2017 07; 17(7):425-440.
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Inactivation of the PBRM1 tumor suppressor gene amplifies the HIF-response in VHL-/- clear cell renal carcinoma. Proc Natl Acad Sci U S A. 2017 01 31; 114(5):1027-1032.
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The VHL Tumor Suppressor Gene: Insights into Oxygen Sensing and Cancer. Trans Am Clin Climatol Assoc. 2017; 128:298-307.
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Targeting HIF2 in Clear Cell Renal Cell Carcinoma. Cold Spring Harb Symp Quant Biol. 2016; 81:113-121.
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Pathways for Oxygen Regulation and Homeostasis: The 2016 Albert Lasker Basic Medical Research Award. JAMA. 2016 Sep 27; 316(12):1252-3.
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PHD3 Loss in Cancer Enables Metabolic Reliance on Fatty Acid Oxidation via Deactivation of ACC2. Mol Cell. 2016 09 15; 63(6):1006-20.
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On-target efficacy of a HIF-2a antagonist in preclinical kidney cancer models. Nature. 2016 11 03; 539(7627):107-111.
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pVHL suppresses kinase activity of Akt in a proline-hydroxylation-dependent manner. Science. 2016 08 26; 353(6302):929-32.
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Paracrine Induction of HIF by Glutamate in Breast Cancer: EglN1 Senses Cysteine. Cell. 2016 Jun 30; 166(1):126-39.
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EGLN1 Inhibition and Rerouting of a-Ketoglutarate Suffice for Remote Ischemic Protection. Cell. 2016 Apr 07; 165(2):497.
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EGLN1 Inhibition and Rerouting of a-Ketoglutarate Suffice for Remote Ischemic Protection. Cell. 2016 Feb 25; 164(5):884-95.
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Fumarate and Succinate Regulate Expression of Hypoxia-inducible Genes via TET Enzymes. J Biol Chem. 2016 Feb 19; 291(8):4256-65.
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Peptidic degron in EID1 is recognized by an SCF E3 ligase complex containing the orphan F-box protein FBXO21. Proc Natl Acad Sci U S A. 2015 Dec 15; 112(50):15372-7.
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Treatment Response Assessment in IDH-Mutant Glioma Patients by Noninvasive 3D Functional Spectroscopic Mapping of 2-Hydroxyglutarate. Clin Cancer Res. 2016 Apr 01; 22(7):1632-41.
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EglN2 associates with the NRF1-PGC1a complex and controls mitochondrial function in breast cancer. EMBO J. 2015 Dec 02; 34(23):2953-70.
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Inhibition of the oxygen sensor PHD2 in the liver improves survival in lactic acidosis by activating the Cori cycle. Proc Natl Acad Sci U S A. 2015 Sep 15; 112(37):11642-7.
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DisABLing kidney cancers caused by fumarate hydratase mutations. Cancer Cell. 2014 Dec 08; 26(6):779-780.
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Genetic evidence of a precisely tuned dysregulation in the hypoxia signaling pathway during oncogenesis. Cancer Res. 2014 Nov 15; 74(22):6554-64.
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A genetic mechanism for Tibetan high-altitude adaptation. Nat Genet. 2014 Sep; 46(9):951-6.
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Phosphorylation of ETS1 by Src family kinases prevents its recognition by the COP1 tumor suppressor. Cancer Cell. 2014 Aug 11; 26(2):222-34.
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Prolyl hydroxylation by EglN2 destabilizes FOXO3a by blocking its interaction with the USP9x deubiquitinase. Genes Dev. 2014 Jul 01; 28(13):1429-44.
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A phase I study of cabozantinib (XL184) in patients with renal cell cancer. Ann Oncol. 2014 Aug; 25(8):1603-8.
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D-2-hydroxyglutarate produced by mutant IDH2 causes cardiomyopathy and neurodegeneration in mice. Genes Dev. 2014 Mar 01; 28(5):479-90.
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SQSTM1 is a pathogenic target of 5q copy number gains in kidney cancer. Cancer Cell. 2013 Dec 09; 24(6):738-50.
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The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science. 2014 Jan 17; 343(6168):305-9.
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Twenty-fifth annual Pezcoller Symposium: Metabolism and tumorigenesis. Cancer Res. 2013 Oct 15; 73(20):6124-7.
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Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature. 2013 Jul 04; 499(7456):43-9.
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What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer. Genes Dev. 2013 Apr 15; 27(8):836-52.
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Influence of metabolism on epigenetics and disease. Cell. 2013 Mar 28; 153(1):56-69.
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(R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible. Science. 2013 Mar 29; 339(6127):1621-5.
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Coordinated repression of cell cycle genes by KDM5A and E2F4 during differentiation. Proc Natl Acad Sci U S A. 2012 Nov 06; 109(45):18499-504.
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Molecular biology. Use and abuse of RNAi to study mammalian gene function. Science. 2012 Jul 27; 337(6093):421-2.
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The VHL/HIF axis in clear cell renal carcinoma. Semin Cancer Biol. 2013 Feb; 23(1):18-25.
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Treatment of erythropoietin deficiency in mice with systemically administered siRNA. Blood. 2012 Aug 30; 120(9):1916-22.
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Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation. Nature. 2012 Feb 15; 483(7390):484-8.
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Cancer and altered metabolism: potential importance of hypoxia-inducible factor and 2-oxoglutarate-dependent dioxygenases. Cold Spring Harb Symp Quant Biol. 2011; 76:335-45.
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Genomic sequencing of colorectal adenocarcinomas identifies a recurrent VTI1A-TCF7L2 fusion. Nat Genet. 2011 Sep 04; 43(10):964-968.
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New insights into the biology of renal cell carcinoma. Hematol Oncol Clin North Am. 2011 Aug; 25(4):667-86.
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Loss of the retinoblastoma binding protein 2 (RBP2) histone demethylase suppresses tumorigenesis in mice lacking Rb1 or Men1. Proc Natl Acad Sci U S A. 2011 Aug 16; 108(33):13379-86.
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Genetic and functional studies implicate HIF1a as a 14q kidney cancer suppressor gene. Cancer Discov. 2011 Aug; 1(3):222-35.
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Clinical and functional properties of novel VHL mutation (X214L) consistent with Type 2A phenotype and low risk of renal cell carcinoma. Clin Genet. 2011 Jun; 79(6):539-45.
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Good COP1 or bad COP1? In vivo veritas. J Clin Invest. 2011 Apr; 121(4):1263-5.
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Mutation analysis of HIF prolyl hydroxylases (PHD/EGLN) in individuals with features of phaeochromocytoma and renal cell carcinoma susceptibility. Endocr Relat Cancer. 2011 Feb; 18(1):73-83.
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FoxOs enforce a progression checkpoint to constrain mTORC1-activated renal tumorigenesis. Cancer Cell. 2010 Nov 16; 18(5):472-84.
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New cancer targets emerging from studies of the Von Hippel-Lindau tumor suppressor protein. Ann N Y Acad Sci. 2010 Oct; 1210:1-7.
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Loss of hypoxia-inducible factor prolyl hydroxylase activity in cardiomyocytes phenocopies ischemic cardiomyopathy. Circulation. 2010 Sep 07; 122(10):1004-16.
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Phosphorylation by casein kinase I promotes the turnover of the Mdm2 oncoprotein via the SCF(beta-TRCP) ubiquitin ligase. Cancer Cell. 2010 Aug 09; 18(2):147-59.
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Reactivation of hepatic EPO synthesis in mice after PHD loss. Science. 2010 Jul 23; 329(5990):407.
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Erlotinib therapy for central nervous system hemangioblastomatosis associated with von Hippel-Lindau disease: a case report. J Neurooncol. 2011 Jan; 101(2):307-10.
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Q&A: Cancer: clues from cell metabolism. Nature. 2010 Jun 03; 465(7298):562-4.
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Prostate cancer: beta control your hormones. Cancer Cell. 2010 Apr 13; 17(4):311-2.
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Slaying RAS with a synthetic lethal weapon. Cell Res. 2010 Feb; 20(2):119-21.
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Control of cyclin D1 and breast tumorigenesis by the EglN2 prolyl hydroxylase. Cancer Cell. 2009 Nov 06; 16(5):413-24.
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Synthetic lethality: a framework for the development of wiser cancer therapeutics. Genome Med. 2009 Oct 27; 1(10):99.
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SDH5 mutations and familial paraganglioma: somewhere Warburg is smiling. Cancer Cell. 2009 Sep 08; 16(3):180-2.
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A feedback loop involving the Phd3 prolyl hydroxylase tunes the mammalian hypoxic response in vivo. Mol Cell Biol. 2009 Nov; 29(21):5729-41.
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HIF2alpha cooperates with RAS to promote lung tumorigenesis in mice. J Clin Invest. 2009 Aug; 119(8):2160-70.
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Patterns of gene expression and copy-number alterations in von-hippel lindau disease-associated and sporadic clear cell carcinoma of the kidney. Cancer Res. 2009 Jun 01; 69(11):4674-81.
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Treatment of kidney cancer: insights provided by the VHL tumor-suppressor protein. Cancer. 2009 May 15; 115(10 Suppl):2262-72.
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Innovations and challenges in renal cancer: summary statement from the Third Cambridge Conference. Cancer. 2009 May 15; 115(10 Suppl):2247-51.
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Kidney cancer: now available in a new flavor. Cancer Cell. 2008 Dec 09; 14(6):423-4.
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A role for mammalian Sin3 in permanent gene silencing. Mol Cell. 2008 Nov 07; 32(3):359-70.
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Kinase requirements in human cells: III. Altered kinase requirements in VHL-/- cancer cells detected in a pilot synthetic lethal screen. Proc Natl Acad Sci U S A. 2008 Oct 28; 105(43):16484-9.
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The von Hippel-Lindau tumour suppressor protein: O2 sensing and cancer. Nat Rev Cancer. 2008 Nov; 8(11):865-73.
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Senescence triggered by the loss of the VHL tumor suppressor. . 2008 Jun 15; 7(12):1709-12.
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Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell. 2008 May 23; 30(4):393-402.
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The kinesin KIF1Bbeta acts downstream from EglN3 to induce apoptosis and is a potential 1p36 tumor suppressor. Genes Dev. 2008 Apr 01; 22(7):884-93.
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VHL loss actuates a HIF-independent senescence programme mediated by Rb and p400. Nat Cell Biol. 2008 Mar; 10(3):361-9.
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Somatic inactivation of the PHD2 prolyl hydroxylase causes polycythemia and congestive heart failure. Blood. 2008 Mar 15; 111(6):3236-44.
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Nineteenth Annual Pezcoller Symposium: hypothesis-driven clinical investigation in cancer. Cancer Res. 2007 Dec 01; 67(23):11102-5.
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pVHL acts as an adaptor to promote the inhibitory phosphorylation of the NF-kappaB agonist Card9 by CK2. Mol Cell. 2007 Oct 12; 28(1):15-27.
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Hypoxia-inducible factor linked to differential kidney cancer risk seen with type 2A and type 2B VHL mutations. Mol Cell Biol. 2007 Aug; 27(15):5381-92.
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The retinoblastoma binding protein RBP2 is an H3K4 demethylase. Cell. 2007 Mar 09; 128(5):889-900.
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Innovations and challenges in renal cell carcinoma: summary statement from the Second Cambridge Conference. Clin Cancer Res. 2007 Jan 15; 13(2 Pt 2):667s-670s.
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The von Hippel-Lindau tumor suppressor protein and clear cell renal carcinoma. Clin Cancer Res. 2007 Jan 15; 13(2 Pt 2):680s-684s.
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The hypoxia-inducible factor 2alpha N-terminal and C-terminal transactivation domains cooperate to promote renal tumorigenesis in vivo. Mol Cell Biol. 2007 Mar; 27(6):2092-102.
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Von Hippel-Lindau disease. Annu Rev Pathol. 2007; 2:145-73.
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The von hippel-lindau tumor suppressor protein: an update. Methods Enzymol. 2007; 435:371-83.
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Retinoblastoma protein and anaphase-promoting complex physically interact and functionally cooperate during cell-cycle exit. Nat Cell Biol. 2007 Feb; 9(2):225-32.
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Molecular pathways in renal cell carcinoma--rationale for targeted treatment. Semin Oncol. 2006 Oct; 33(5):588-95.
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Failure to prolyl hydroxylate hypoxia-inducible factor alpha phenocopies VHL inactivation in vivo. EMBO J. 2006 Oct 04; 25(19):4650-62.
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Cell biology: divining cancer cell weaknesses. Nature. 2006 May 04; 441(7089):32-4.
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Clusterin is a secreted marker for a hypoxia-inducible factor-independent function of the von Hippel-Lindau tumor suppressor protein. Am J Pathol. 2006 Feb; 168(2):574-84.
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Recent insights into the molecular pathogenesis of pheochromocytoma and paraganglioma. Endocr Pathol. 2006; 17(2):97-106.
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Mouse model for noninvasive imaging of HIF prolyl hydroxylase activity: assessment of an oral agent that stimulates erythropoietin production. Proc Natl Acad Sci U S A. 2006 Jan 03; 103(1):105-10.
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The concept of synthetic lethality in the context of anticancer therapy. Nat Rev Cancer. 2005 Sep; 5(9):689-98.
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The von Hippel-Lindau protein, HIF hydroxylation, and oxygen sensing. Biochem Biophys Res Commun. 2005 Dec 09; 338(1):627-38.
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Neuronal apoptosis linked to EglN3 prolyl hydroxylase and familial pheochromocytoma genes: developmental culling and cancer. Cancer Cell. 2005 Aug; 8(2):155-67.
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The v-Jun point mutation allows c-Jun to escape GSK3-dependent recognition and destruction by the Fbw7 ubiquitin ligase. Cancer Cell. 2005 Jul; 8(1):25-33.
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Binding of pRB to the PHD protein RBP2 promotes cellular differentiation. Mol Cell. 2005 Jun 10; 18(6):623-35.
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ROS: really involved in oxygen sensing. Cell Metab. 2005 Jun; 1(6):357-8.
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Bioluminescent imaging of ubiquitin ligase activity: measuring Cdk2 activity in vivo through changes in p27 turnover. Methods Enzymol. 2005; 399:530-49.
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The von Hippel-Lindau tumor suppressor protein: roles in cancer and oxygen sensing. Cold Spring Harb Symp Quant Biol. 2005; 70:159-66.
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Proline hydroxylation and gene expression. Annu Rev Biochem. 2005; 74:115-28.
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Role of VHL gene mutation in human cancer. J Clin Oncol. 2004 Dec 15; 22(24):4991-5004.
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Inhibition of vascular endothelial growth factor with a sequence-specific hypoxia response element antagonist. Proc Natl Acad Sci U S A. 2004 Nov 30; 101(48):16768-73.
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Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev. 2004 Dec 01; 18(23):2893-904.
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The von Hippel-Lindau tumor suppressor gene and kidney cancer. Clin Cancer Res. 2004 Sep 15; 10(18 Pt 2):6290S-5S.
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Innovations and challenges in renal cancer: consensus statement from the first international conference. Clin Cancer Res. 2004 Sep 15; 10(18 Pt 2):6277S-81S.
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Dysregulation of HIF and VEGF is a unifying feature of the familial hamartoma syndromes. Cancer Cell. 2004 Jul; 6(1):7-10.
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Bioluminescent imaging of Cdk2 inhibition in vivo. Nat Med. 2004 Jun; 10(6):643-8.
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Proceedings of the Oxygen Homeostasis/Hypoxia Meeting. Cancer Res. 2004 May 01; 64(9):3350-6.
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Fifteenth annual Pezcoller symposium: molecular in vivo visualization of cancer cells. Cancer Res. 2004 Apr 15; 64(8):2929-33.
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pVHL modification by NEDD8 is required for fibronectin matrix assembly and suppression of tumor development. Mol Cell Biol. 2004 Apr; 24(8):3251-61.
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Gleevec: prototype or outlier? Sci STKE. 2004 Mar 16; 2004(225):pe12.
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Degradation of the SCF component Skp2 in cell-cycle phase G1 by the anaphase-promoting complex. Nature. 2004 Mar 11; 428(6979):194-8.
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Analysis of von Hippel-Lindau hereditary cancer syndrome: implications of oxygen sensing. Methods Enzymol. 2004; 381:320-35.
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Inhibition of HIF2alpha is sufficient to suppress pVHL-defective tumor growth. PLoS Biol. 2003 Dec; 1(3):E83.
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The von Hippel-Lindau gene, kidney cancer, and oxygen sensing. J Am Soc Nephrol. 2003 Nov; 14(11):2703-11.
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Mouse reporter strain for noninvasive bioluminescent imaging of cells that have undergone Cre-mediated recombination. Mol Imaging. 2003 Oct; 2(4):297-302.
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TSC2 regulates VEGF through mTOR-dependent and -independent pathways. Cancer Cell. 2003 Aug; 4(2):147-58.
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The von Hippel-Lindau protein, vascular endothelial growth factor, and kidney cancer. N Engl J Med. 2003 Jul 31; 349(5):419-21.
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E2F1 as a target: promoter-driven suicide and small molecule modulators. . 2003 Jul-Aug; 2(4 Suppl 1):S48-54.
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Chemosensitivity linked to p73 function. Cancer Cell. 2003 Apr; 3(4):403-10.
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Gene expression profiling in a renal cell carcinoma cell line: dissecting VHL and hypoxia-dependent pathways. Mol Cancer Res. 2003 Apr; 1(6):453-62.
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HIF hydroxylation and the mammalian oxygen-sensing pathway. J Clin Invest. 2003 Mar; 111(6):779-83.
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The von Hippel-Lindau tumor suppressor protein: new insights into oxygen sensing and cancer. Curr Opin Genet Dev. 2003 Feb; 13(1):55-60.
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VHL and kidney cancer. Methods Mol Biol. 2003; 222:167-83.
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Detection of peptides, proteins, and drugs that selectively interact with protein targets. Genome Res. 2002 Nov; 12(11):1785-91.
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Biochemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible factor. Proc Natl Acad Sci U S A. 2002 Oct 15; 99(21):13459-64.
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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. Ophthalmology. 2002 Sep; 109(9):1745-51.
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Molecular basis of the VHL hereditary cancer syndrome. Nat Rev Cancer. 2002 Sep; 2(9):673-82.
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Using cancer genetics to guide the selection of anticancer drug targets. Curr Opin Pharmacol. 2002 Aug; 2(4):366-73.
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How oxygen makes its presence felt. Genes Dev. 2002 Jun 15; 16(12):1441-5.
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Structure of an HIF-1alpha -pVHL complex: hydroxyproline recognition in signaling. Science. 2002 Jun 07; 296(5574):1886-9.
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The human p73 promoter: characterization and identification of functional E2F binding sites. Neoplasia. 2002 May-Jun; 4(3):195-203.
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Inhibition of HIF is necessary for tumor suppression by the von Hippel-Lindau protein. Cancer Cell. 2002 Apr; 1(3):237-46.
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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. Mol Cell Biol. 2002 Mar; 22(6):1947-60.
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An intact NEDD8 pathway is required for Cullin-dependent ubiquitylation in mammalian cells. . 2002 Feb; 3(2):177-82.
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Degradation of p53 by adenovirus E4orf6 and E1B55K proteins occurs via a novel mechanism involving a Cullin-containing complex. Genes Dev. 2001 Dec 01; 15(23):3104-17.
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Molecular pathogenesis of the von Hippel-Lindau hereditary cancer syndrome: implications for oxygen sensing. Cell Growth Differ. 2001 Sep; 12(9):447-55.
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p53 family update: p73 and p63 develop their own identities. Cell Growth Differ. 2001 Jul; 12(7):337-49.
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Differential control of transcription by DNA-bound cyclins. Mol Biol Cell. 2001 Jul; 12(7):2207-17.
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Human cytotrophoblast expression of the von Hippel-Lindau protein is downregulated during uterine invasion in situ and upregulated by hypoxia in vitro. Dev Biol. 2001 May 15; 233(2):526-36.
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von Hippel-Lindau protein mutants linked to type 2C VHL disease preserve the ability to downregulate HIF. Hum Mol Genet. 2001 May 01; 10(10):1019-27.
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HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science. 2001 Apr 20; 292(5516):464-8.
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The von Hippel-Lindau tumor suppressor gene. Exp Cell Res. 2001 Mar 10; 264(1):117-25.
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Role of the newer p53 family proteins in malignancy. Apoptosis. 2001 Feb-Apr; 6(1-2):17-29.
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The von Hippel-Lindau tumor suppressor protein. Curr Opin Genet Dev. 2001 Feb; 11(1):27-34.
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Preferential retention of codon 72 arginine p53 in squamous cell carcinomas of the vulva occurs in cancers positive and negative for human papillomavirus. Cancer Res. 2000 Dec 15; 60(24):6875-7.
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Cells degrade a novel inhibitor of differentiation with E1A-like properties upon exiting the cell cycle. Mol Cell Biol. 2000 Dec; 20(23):8889-902.
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Suppression of tumor growth through disruption of hypoxia-inducible transcription. Nat Med. 2000 Dec; 6(12):1335-40.
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Cyclin D1 suppresses retinoblastoma protein-mediated inhibition of TAFII250 kinase activity. Oncogene. 2000 Nov 23; 19(50):5703-11.
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A common E2F-1 and p73 pathway mediates cell death induced by TCR activation. Nature. 2000 Oct 05; 407(6804):642-5.
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Role for the p53 homologue p73 in E2F-1-induced apoptosis. Nature. 2000 Oct 05; 407(6804):645-8.
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Myc-enhanced expression of Cul1 promotes ubiquitin-dependent proteolysis and cell cycle progression. Genes Dev. 2000 Sep 01; 14(17):2185-91.
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Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein. Nat Cell Biol. 2000 Jul; 2(7):423-7.
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p63 and p73: old members of a new family. Biochim Biophys Acta. 2000 May 17; 1470(3):M93-M100.
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A common polymorphism acts as an intragenic modifier of mutant p53 behaviour. Nat Genet. 2000 May; 25(1):47-54.
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The p53 gene family. Oncogene. 1999 Dec 13; 18(53):7701-5.
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Synthetic peptides define critical contacts between elongin C, elongin B, and the von Hippel-Lindau protein. J Clin Invest. 1999 Dec; 104(11):1583-91.
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Choosing anticancer drug targets in the postgenomic era. J Clin Invest. 1999 Dec; 104(11):1503-6.
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Taking aim at novel molecular targets in cancer therapy. J Clin Invest. 1999 Dec; 104(11):1495.
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Functions of the retinoblastoma protein. Bioessays. 1999 Nov; 21(11):950-8.
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RBP1 recruits both histone deacetylase-dependent and -independent repression activities to retinoblastoma family proteins. Mol Cell Biol. 1999 Oct; 19(10):6632-41.
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The von Hippel-Lindau tumor suppressor gene inhibits hepatocyte growth factor/scatter factor-induced invasion and branching morphogenesis in renal carcinoma cells. Mol Cell Biol. 1999 Sep; 19(9):5902-12.
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The tyrosine kinase c-Abl regulates p73 in apoptotic response to cisplatin-induced DNA damage. Nature. 1999 Jun 24; 399(6738):806-9.
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The von Hippel-Lindau tumour suppressor protein: new perspectives. Mol Med Today. 1999 Jun; 5(6):257-63.
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Cancer. Many vessels, faulty gene. Nature. 1999 May 20; 399(6733):203-4.
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MDM2 suppresses p73 function without promoting p73 degradation. Mol Cell Biol. 1999 May; 19(5):3257-66.
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Third International Meeting on von Hippel-Lindau disease. Cancer Res. 1999 May 01; 59(9):2251-3.
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Rbx1, a component of the VHL tumor suppressor complex and SCF ubiquitin ligase. Science. 1999 Apr 23; 284(5414):657-61.
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Structure of the VHL-ElonginC-ElonginB complex: implications for VHL tumor suppressor function. Science. 1999 Apr 16; 284(5413):455-61.
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Selective killing of transformed cells by cyclin/cyclin-dependent kinase 2 antagonists. Proc Natl Acad Sci U S A. 1999 Apr 13; 96(8):4325-9.
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The emerging p53 gene family. J Natl Cancer Inst. 1999 Apr 07; 91(7):594-8.
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Retinoblastoma protein contains a C-terminal motif that targets it for phosphorylation by cyclin-cdk complexes. Mol Cell Biol. 1999 Feb; 19(2):1068-80.
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The Elongin BC complex interacts with the conserved SOCS-box motif present in members of the SOCS, ras, WD-40 repeat, and ankyrin repeat families. Genes Dev. 1998 Dec 15; 12(24):3872-81.
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Negative control elements of the cell cycle in human tumors. Curr Opin Cell Biol. 1998 Dec; 10(6):791-7.
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von Hippel-Lindau gene-mediated growth suppression and induction of differentiation in renal cell carcinoma cells grown as multicellular tumor spheroids. Cancer Res. 1998 Nov 01; 58(21):4957-62.
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Viral oncoproteins discriminate between p53 and the p53 homolog p73. Mol Cell Biol. 1998 Nov; 18(11):6316-24.
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The VHL tumour-suppressor gene paradigm. Trends Genet. 1998 Oct; 14(10):423-6.
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pVHL19 is a biologically active product of the von Hippel-Lindau gene arising from internal translation initiation. Proc Natl Acad Sci U S A. 1998 Sep 29; 95(20):11661-6.
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Another p53 Doppelgänger? Science. 1998 Jul 03; 281(5373):57-8.
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Functions of the von Hippel-Lindau tumour suppressor protein. J Intern Med. 1998 Jun; 243(6):535-9.
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The von Hippel-Lindau tumor suppressor protein is required for proper assembly of an extracellular fibronectin matrix. Mol Cell. 1998 Jun; 1(7):959-68.
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Regulation of hypoxia-inducible mRNAs by the von Hippel-Lindau tumor suppressor protein requires binding to complexes containing elongins B/C and Cul2. Mol Cell Biol. 1998 Feb; 18(2):732-41.
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Stable binding to E2F is not required for the retinoblastoma protein to activate transcription, promote differentiation, and suppress tumor cell growth. Genes Dev. 1998 Jan 01; 12(1):95-106.
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Alterations in G1/S cell-cycle control contributing to carcinogenesis. Ann N Y Acad Sci. 1997 Dec 29; 833:29-33.
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von Hippel-Lindau disease. Medicine (Baltimore). 1997 Nov; 76(6):381-91.
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Role of the retinoblastoma protein in the pathogenesis of human cancer. J Clin Oncol. 1997 Nov; 15(11):3301-12.
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Tumor-selective transgene expression in vivo mediated by an E2F-responsive adenoviral vector. Nat Med. 1997 Oct; 3(10):1145-9.
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p73 is a simian [correction of human] p53-related protein that can induce apoptosis. Nature. 1997 Sep 11; 389(6647):191-4.
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The molecular basis of von Hippel-Lindau disease. Mol Med. 1997 May; 3(5):289-93.
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Immunostaining of the von Hippel-Lindau gene product in normal and neoplastic human tissues. Hum Pathol. 1997 Apr; 28(4):459-64.
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Fluorescence-activated cell sorting of transfected cells. Methods Enzymol. 1997; 283:59-72.
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Recent insights into the functions of the retinoblastoma susceptibility gene product. Cancer Invest. 1997; 15(3):243-54.
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Identification of a cyclin-cdk2 recognition motif present in substrates and p21-like cyclin-dependent kinase inhibitors. Mol Cell Biol. 1996 Dec; 16(12):6623-33.
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Negative regulation of hypoxia-inducible genes by the von Hippel-Lindau protein. Proc Natl Acad Sci U S A. 1996 Oct 01; 93(20):10595-9.
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Structure and partial genomic sequence of the human E2F1 gene. Gene. 1996 Sep 16; 173(2):163-9.
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A maize cDNA encoding a member of the retinoblastoma protein family: involvement in endoreduplication. Proc Natl Acad Sci U S A. 1996 Aug 20; 93(17):8962-7.
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RB [corrected] as a modulator of transcription. Biochim Biophys Acta. 1996 Aug 08; 1288(1):M1-5.
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Expression pattern of the von Hippel-Lindau protein in human tissues. Lab Invest. 1996 Aug; 75(2):231-8.
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A conserved region of unknown function participates in the recognition of E2F family members by the adenovirus E4 ORF 6/7 protein. Virology. 1996 Jun 01; 220(1):78-90.
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E2F-1 functions in mice to promote apoptosis and suppress proliferation. Cell. 1996 May 17; 85(4):549-61.
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The cellular effects of E2F overexpression. Curr Top Microbiol Immunol. 1996; 208:79-93.
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A potent transrepression domain in the retinoblastoma protein induces a cell cycle arrest when bound to E2F sites. Proc Natl Acad Sci U S A. 1995 Dec 05; 92(25):11544-8.
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Binding of the von Hippel-Lindau tumor suppressor protein to Elongin B and C. Science. 1995 Sep 08; 269(5229):1444-6.
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Transcription of the E2F-1 gene is rendered cell cycle dependent by E2F DNA-binding sites within its promoter. Mol Cell Biol. 1995 Aug; 15(8):4660.
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Tumour suppression by the human von Hippel-Lindau gene product. Nat Med. 1995 Aug; 1(8):822-6.
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Transcriptional control by E2F. Semin Cancer Biol. 1995 Apr; 6(2):99-108.
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The transcription factor E2F-1 is a downstream target of RB action. Mol Cell Biol. 1995 Feb; 15(2):742-55.
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Deregulated transcription factor E2F-1 expression leads to S-phase entry and p53-mediated apoptosis. Proc Natl Acad Sci U S A. 1994 Nov 08; 91(23):10918-22.
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Transcription of the E2F-1 gene is rendered cell cycle dependent by E2F DNA-binding sites within its promoter. Mol Cell Biol. 1994 Oct; 14(10):6607-15.
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Negative regulation of the growth-promoting transcription factor E2F-1 by a stably bound cyclin A-dependent protein kinase. Cell. 1994 Jul 15; 78(1):161-72.
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Cloning, chromosomal location, and characterization of mouse E2F1. Mol Cell Biol. 1994 Mar; 14(3):1861-9.
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Structural and functional contributions to the G1 blocking action of the retinoblastoma protein. (the 1992 Gordon Hamilton Fairley Memorial Lecture). Br J Cancer. 1993 Aug; 68(2):264-8.
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E2F-1-mediated transactivation is inhibited by complex formation with the retinoblastoma susceptibility gene product. Proc Natl Acad Sci U S A. 1993 Aug 01; 90(15):6914-8.
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Regulation of the Ets-related transcription factor Elf-1 by binding to the retinoblastoma protein. Science. 1993 May 28; 260(5112):1330-5.
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A protein synthesis-dependent increase in E2F1 mRNA correlates with growth regulation of the dihydrofolate reductase promoter. Mol Cell Biol. 1993 Mar; 13(3):1610-8.
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Expression cloning of a cDNA encoding a retinoblastoma-binding protein with E2F-like properties. Cell. 1992 Jul 24; 70(2):351-64.
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Identification of a growth suppression domain within the retinoblastoma gene product. Genes Dev. 1992 Jun; 6(6):953-64.
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The T/E1A-binding domain of the retinoblastoma product can interact selectively with a sequence-specific DNA-binding protein. Cell. 1991 Jun 14; 65(6):1073-82.
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Identification of cellular proteins that can interact specifically with the T/E1A-binding region of the retinoblastoma gene product. Cell. 1991 Feb 08; 64(3):521-32.
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RB associates with an E2F-like, sequence-specific DNA-binding protein. Cold Spring Harb Symp Quant Biol. 1991; 56:187-95.
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Definition of the minimal simian virus 40 large T antigen- and adenovirus E1A-binding domain in the retinoblastoma gene product. Mol Cell Biol. 1990 Jul; 10(7):3761-9.
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