William G. Kaelin Jr., MD
Professor of Medicine, Harvard Medical School
Department
Medical Oncology/Molecular and Cellular
Area of Research
Functions of Tumor Suppressor Proteins
Contact Information
William G. Kaelin Jr., MDDana-Farber Cancer Institute
44 Binney Street
Mayer 457
Boston, MA 02115
Office phone: (617) 632-3975
Fax: (617) 632-4760
E-mail: william_kaelin@dfci.harvard.edu
Preferred contact method: office phone
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.
Recent Awards
- Paul Marks Prizes for Cancer Research, Memorial Sloan-Kettering, 2001
- Investigator, Howard Hughes Medical Institute, 1998
- Richard A. Smith Prize, DFCI, 1996-1997
- James S. McDonnell Scholar, 1993
Biography
Dr. Kaelin received his MD from Duke University in 1982 and was a house officer in internal medicine at Johns Hopkins Hospital. He was a medical oncology clinical fellow at DFCI 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 DFCI in 1992 and a Howard Hughes Medical Institute investigator in 1998.
Select Publications
- Lee S, Nakamura E, Yang H, Wei W, Linggi MS, Sajan MP, Farese RV, Freeman RS, Carter BD, Kaelin WG Jr, Schlisio S. Neuronal apoptosis linked to EglN3 prolyl hydroxylase and familial pheochromocytoma genes: developmental culling and cancer. Cancer Cell 2005;8:155-67.
- Kondo K, Kim WY, Lechpammer M, Kaelin WG Jr. Inhibition of HIF2alpha is sufficient to suppress pVHL-defective tumor growth. PLoS Biol 2003;1:E83.
- Wei W, Jin J, Schlisio S, Harper JW, Kaelin WG Jr. The v-Jun point mutation allows c-Jun to escape GSK3-dependent recognition and destruction by the Fbw7 ubiquitin ligase. Cancer Cell 2005;8:25-33.
- Benevolenskaya EV, Murray HL, Branton P, Young RA, Kaelin WG Jr. Binding of pRB to the PHD protein RBP2 promotes cellular differentiation. Mol Cell 2005;18:623-35.
- Olenyuk BZ, Zhang GJ, Klco JM, Nickols NG, Kaelin WG Jr, Dervan PB. Inhibition of vascular endothelial growth factor with a sequence-specific hypoxia response element antagonist. Proc Natl Acad Sci U S A 2004;101:16768-73.
- Brugarolas J, Lei K, Hurley RL, Manning BD, Reiling JH, Hafen E, Witters LA, Ellisen LW, Kaelin WG Jr. Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev 2004;18:2893-904.
- Zhang GJ, Safran M, Wei W, Sorensen E, Lassota P, Zhelev N, Neuberg DS, Shapiro G, Kaelin WG Jr. Bioluminescent imaging of Cdk2 inhibition in vivo. Nat Med 2004;10:643-8.
- Wei W, Ayad NG, Wan Y, Zhang GJ, Kirschner MW, Kaelin WG Jr. Degradation of the SCF component Skp2 in cell-cycle phase G1 by the anaphase-promoting complex. Nature 2004;428:194-8.
- Kaelin WG. The concept of synthetic lethality in the context of anticancer therapy. Nat Rev Cancer 2005;5:689-98.
