William G. Kaelin Jr., MD
Office phone: 617-632-3975
Website: William Kaelin Laboratory
Preferred contact method: office phone
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Area of ResearchFunctions of Tumor Suppressor Proteins
Dana-Farber Cancer Institute
450 Brookline Avenue
Boston, MA 02215
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.
- Elected to Association of American Physicians, 2012
- Scientific Grand Prix, Foundation Lefoulon-Delalande, Institut de France (co-recipient), 2012
- Stanley J. Korsmeyer Award, ASCI (co-recipient), 2012
- Alfred Knudson Award in Cancer Genetics, 2011
- Canada Gairdner Award, 2010
- Elected to National Academy of Sciences, 2010
- AICR Colin Thomson Medal, 2008
- Elected to Institute of Medicine, 2007
ResearchFunctions 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.
- Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, Salic A, Asara JM, Lane WS, Kaelin WG Jr. HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 2001; 292:464-8.
- Klose RJ, Yan Q, Tothova Z, Yamane K, Erdjument-Bromage H, Tempst P, Gilliland DG, Zhang Y, Kaelin WG Jr. The retinoblastoma binding protein RBP2 is an H3K4 demethylase. Cell. 2007; 128:889-900
- Bommi-Reddy A, Almeciga I, Sawyer J, Geisen C, Li W, Harlow E, Kaelin WG Jr, Grueneberg DA. Kinase requirements in human cells: III. Altered kinase requirements in VHL-/- cancer cells detected in a pilot synthetic lethal screen. Proc Natl Acad Sci USA. 2008; 105(43):16484-9.
- Schlisio S, Kenchappa RS, Vredeveld LC, George RE, Stewart R, Greulich H, Shahriari K, Nguyen NV, Pigny P, Dahia PL, Pomeroy SI, Maris JM, Look AT, Meyerson M, Peeper DS, Carter BD, Kaelin WG Jr. The kinesin KIF1Bbeta acts downstream from EglN3 to induce apoptosis and is a potential 1p36 tumor suppressor. Genes Dev. 2008; 22(7):884-93
- Zhang Q, Gu J, Li L, Liu J, Luo B, Cheung HW, Boehm JS, Ni M, Geisen C, Root DE, Polyak K, Brown M, Richardson AL, Hahn WC, Kaelin WG Jr, Bommi-Reddy A. Control of cyclin D1 and breast tumorigenesis by the EgIN2 prolyl hydroxylase. Cancer Cell. 2009 Nov 6;16(5):413-24.
- Moslehi J, Minamishima YA, Shi J, Neuberg D, Charytan D, Padera R, Signoretti S, Liao R, and Kaelin WG. Loss of HIF Prolyl Hydroxylase Activity in Cardiomyocytes Phenocopies Ischemic Cardiomyopathy. Circulation 2010 Sep 7;122(10):1004-16
- Minimishima YA and Kaelin WG. Reactivation of Hepatic EPO Synthesis in Mice After PHD Loss Science 2010 Jul 23;329(5990):407.
- Shen C, Beroukhim R, Schumacher SE, Zhou J, Chang M. Signoretti S, Kaelin WG Jr. Genetic and Functional Studies Implicate HIF1a as a 14q Kidney Cancer Suppressor Gene. Cancer Discov. 2011 Aug; 1(3):222-35.
- Lin W, Cao J, Liu J, Beshiri ML, Fujiwara Y, Francis J, Cherniack AD, Geisen C, Blair LP, Zou MR, Shen X, Kawamori D, Liu Z, Grisanzio C, Watanabe H, Minamishima YA, Zhang Q, Kulkarni RN, Signoretti S, Rodig SJ, Bronson RT, Orkin SH, Tuck DP, Benevolenskaya EV, Meyerson M, Kaelin WG Jr, Yan Q. Loss of the retinoblastoma binding protein 2 (RBP2) histone demethylase suppresses tumorigenesis in mice lacking Rb1 or Men1. Proc Natl Acad Sci USA. 2011 Aug 16;108(33):13379-86.
- Koivunen P, Lee S, Duncan CG, Lopez G, Lu G, Ramkissoon S, Losman J, Joensuu P, Bergmann U, Gross S, Travins J, Weiss S, Looper R, Ligon KL, Verhaak RGW, Yan H, Kaelin WG Jr. Transformation by the R Enantiomer of 2-Hydroxyglutarate Linked to EgIN Activation. Nature 2012 Feb 15;483(7390):484-8.
- Baik, Alan, Medical Student
- Briggs, Kimberly, PhD
- Chakraborty, Abhishek, PhD
- Gao, Wenhua, PhD
- Li, Lianjie, MD, PhD
- Liberzon, Ella, PhD
- Losman, Julie-Aurore, MD, PhD
- Lu, Gang, PhD
- Moslehi, Javid, MD
- Olenchock, Benjamin, MD, PhD
- Shen, Chuan, PhD
- Zhang, Cuiyan, PhD
- Zhang, Qing, PhD