Waldemar Von Zedtwitz Professor and Vice Chairman of Genetics
Professor of Therapeutic Radiology
Scientific Director, Yale Cancer Center

* B.S. Yale University, 1974
* M.D. Johns Hopkins University School of Medicine, 1978
* Ph.D. Johns Hopkins University School of Medicine, 1981

Research Interests:

* Molecular Biology of Tumor Viruses
* Mechanisms of Viral Carcinogenesis
* Molecular Basis of Cell Growth Regulation and Senescence
* Manipulating Cells and Viruses with Artificial Transmembrane Proteins

Honors:

* Fellow, American Academy of Microbiology
* Fellow, American Association for the Advancement of Science

The DiMaio laboratory is interested in cell proliferation and cancer. We primarily study proteins from the papillomaviruses, which are an important cause of human cancer. As well as studying the role of papillomavirus proteins in carcinogenesis, we are using the viral proteins as models to develop new approaches to modulate cell behavior. We hope that these studies will provide important new insights into carcinogensis and cell growth control and suggest new approaches for treating cancer and other diseases.

Current Research:

One major interest of the laboratory is to determine the mechanism of action of viral oncogenes and to exploit this knowledge to develop new approaches to manipulate cell behavior. We showed that the very small transmembrane E5 protein of bovine papillomavirus binds to and activates the cellular platelet-derived growth factor receptor, resulting in growth stimulation and tumorigenic transformation of cells. These findings demonstrated that receptor tyrosine kinases can be activated by proteins that do not resemble their normal ligands. We have shown that direct interactions involving specific transmembrane and juxtamembrane amino acids in the E5 protein and the PDGF receptor result in dimerization and trans-phosphorylation of the receptor, and recruitment of cellular signaling molecules into a signal transduction complex. Experiments are underway to determine whether the same intracellular pathways are mobilized when the PDGF receptor is activated by PDGF, by the E5 protein, or by activating mutations in the receptor. Using the E5 protein as a model, we have also devised a genetic screen that allows us to construct and identify small proteins with randomized transmembrane domains that can induce the dimerization of growth factor receptors. We believe that this approach can be extended to identify constructed small transmembrane proteins that interact with various cellular and viral transmembrane proteins. Because 30% of all cell proteins are integral membrane proteins, this approach may allow us to influence many aspects of cell behavior including susceptibility to virus infection. Taken together, these experiments should allow us to elucidate the general rules that govern the assembly of transmembrane protein complexes, to determine the mechanism of growth factor receptor activation, and to develop new approaches to modulate cell function.

The other major interest in the laboratory is to investigate the role of the human papillomavirus E6 and E7 proteins in cervical cancer. We have shown that expression of the papillomavirus E2 transcription factor represses HPV E6 and E7 expression in human cervical cancer cells. This causes transient activation of endogenous p53 and retinoblastoma tumor suppressor pathways, dramatic growth inhibition, and rapid induction of the senescent phenotype. These results demonstrate that continued expression of the HPV oncogenes is required to maintain the proliferative state of these cancer cells and imply that manipulations that activate cellular tumor suppressor and senescence pathways may be an approach to treat cancer. We are now using this system to identify and characterize the separate contributions of the E6 and E7 proteins to the maintenance of the malignant state and the control of cell proliferation, senescence and apoptosis. We are also attempting to identify novel genetic elements that interfere with the action of the HPV oncogenes or the cellular pathways that lead to senescence. We are also interested in exploiting the viral basis of some human cancer to develop novel methods to treat these tumors. Toward this end, we have developed restriction enzymes that specifically cleave viral DNA in cancer cells, as well as viral vaccines that can eliminate cancer cells in animal models.