William G. Kaelin, Jr.
Harvard University
|
Primary Section: 41, Medical Genetics, Hematology, and Oncology Membership Type:
Member
(elected 2010)
|
Research Interests
I am trained as a medical oncologist and molecular biologist. As a postdoctoral fellow I determined that tumor suppression by the retinoblastoma protein is due, at least partly, to its ability to bind to members of the E2F family of cell-cycle regulatory transcription factors and cloned the first member of the E2F family, E2F1. As an independent investigator I have focused primarily on the von Hippel-Lindau tumor suppressor protein (pVHL), which is defective in the most common form of kidney cancer. We showed that pVHL is part of an ubiquitin ligase complex that, in the presence of oxygen, targets the HIF transcription factor for proteasomal degradation. Moreover, we showed that the binding of pVHL to HIF requires that HIF be prolyl hydroxylated by oxygen-dependent enzymes, thereby providing a mechanism by which cells sense and adapt to changes in oxygen. Our current focus is to identify additional pVHL functions, to identify genetic alterations that cooperate with pVHL loss to cause cancer, and to determine if other intracellular proteins are subject to hydroxylation. We are also using genetic and pharmacologic tools to determine if HIF stabilization would have salutary effects in the setting of anemia or ischemic diseases.
