Daniel DiMaio

Professor of Genetics

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

Honors:

Mallinckrodt Scholar Award
NIH Merit Award
Fellow, American Academy of Microbiology

We are interested in proteins that control cell proliferation. Many of the proteins we study are derived from tumor viruses, particularly papillomaviruses, which are an important cause of human cancers. We hope that these studies will provide important new insights into carcinogensis and cell growth control and may eventually suggest new approaches for treating cancer and other diseases.

Current Research

We have shown 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 cell transformation. This finding establishes that receptor tyrosine kinases can be activated by proteins that do not resemble their normal ligands. A variety of genetic, biochemical, and structural studies are underway to determine the mechanism by which the E5 protein activates the PDGF receptor. We are testing the model 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. We have also devised a genetic screen that should allow us to construct and identify novel proteins based on the E5 protein that can induce the dimerization of various transmembrane proteins. We have also identified a regulatory domain in the juxtamembrane region of the PDGF receptor that restrains its catalytic activity, and we are conducting experiments to establish the biochemical basis for this activity. Experiments are also 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. Taken together, these experiments should allow us to discern the general rules that govern the assembly of transmembrane protein complexes and the activation of growth factor receptors.

The other major interest in the laboratory is the investigation of the role of the human papillomavirus E6 and E7 proteins in cervical carcinogenesis. 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 tumor suppressor pathways, dramatic growth inhibition, and rapid induction of the senescent phenotype. These experiments 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 the separate contributions of the E6 and E7 proteins to the maintenance of the malignant state. In addition, we are characterizing variant cells that continue to proliferate despite repression of the HPV oncogenes, in an attempt to identify novel genes involved in cell growth control. We are also adapting this system to allow us to identify novel agents that interfere with the action of the HPV oncogenes or the cellular pathways that lead to senescence.

[60K GIF]

A papillomavirus regulatory protein represses HPV oncogene expression and cancer cell growth. HeLa cervical cancer cells were infected with a recombinant virus that expresses a papillomavirus E2 protein. This results in dramatic repression of HPV 18 gene expression in the cancer cells, shown in the Northern blot in the inset and graphed as the percentage of the signal from mock-infected cells (solid line). This is followed shortly thereafter with profound inhibition of cell proliferation (dashed line).

Representative Publications:

Hwang, E.-S., Naeger, L.K., and DiMaio, D. (1996) Activation of the endogenous p53 growth inhibitory pathway in HeLa cells by expression of the bovine papillomavirus E2 regulatory protein. Oncogene 12: 795-803.

Lai, C.C., Henningson, C. and DiMaio, D. (1998) Bovine papillomavirus E5 protein induces oligomerization and trans-phosphorylation of the platelet-derived growth factor beta receptor. Proc. Natl. Acad. Sci. USA 95: 15241-15246.

Irusta, P.M. and DiMaio, D. (1998) A single amino acid substitution in a WW-like domain of diverse members of the PDGF receptor subfamily of tyrosine kinases causes constitutive receptor activation. EMBO J. 17: 6912-6923.

Klein, O., Polack, G.W.,Surtin, T., Kegler-Ebo, D., Smith, S.O. and DiMaio, D. (1998) Role of glutamine 17 of the bovine papillomavirus E5 protein in platelet-derived growht factor beta receptor activation and cell transformation. J. Virol. 72: 8921-8932.

Naeger, L.K., Goodwin, E., Hwang, E.-S., DeFillipis, R.A., H. Zhang, and DiMaio, D. (1999) Bovine papillomavirus E2 protein activates a complex growth-inhibitory program in p53-negative HT-3 cervical carcinoma cells that includes repression of cyclin A and cdc25A phosphatase genes and accumulation of hypophosphorylated retinoblastoma protein. Cell Growth and Differentiation 10: 413-422.

Lai, C.C., Henningson, C., and DiMaio, D. (2000) The bovine papillomavirus E5 protein induces the formation of signal transduction complexes containing dimeric activated PDGF b receptor and associated signaling molecules. Journal of Biological Chemistry 275: 9832-9840.

Wu, L., Goodwin, E., Naeger, L.K., Vigo, E., Galaktionov, K., Helin, K., and DiMaio, D. (2000) E2F/Rb repressor complexes assemble and inhibit cdc25A transcription in cervical carcinoma cells following repression of human papillomavirus oncogene expression. Mol. Cell. Biol. 20: 7059-7067.

Goodwin, E., Yang, E., DiMaio, D., and Hwang, E.-S. (2000) Rapid induction of senescence in cervical carcinoma cells by repression of human papillomavirus oncogene expression. Proc. Natl. Acad. Sci. (USA) 97: 10978-10983.

Goodwin, E. and DiMaio, D. (2000) Repression of human papillomavirus oncogene expression in HeLa cervical carcinoma cells causes the orderly reactivation of dormant tumor suppressor pathways. Proc. Natl. Acad. Sci. (USA), 97: 12513-12518.

Updated 30 August 2002