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.