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DANIEL DIMAIO

Our major research interests are in the general areas of viral carcinogenesis, transmembrane protein interactions, cell cycle control, and cellular senescence.  We focus on the transforming proteins encoded by the papillomaviruses, important tumor viruses, and the cellular targets of these proteins.

The E5 protein of bovine papillomavirus is an extremely short transmembrane protein that transforms cells in culture.  We discovered that the E5 protein transforms cells by activating the platelet-derived growth factor ß receptor, thereby identifying a novel mechanism of DNA virus transformation and demonstrating that receptor tyrosine kinases can be activated by small proteins unrelated to their normal ligands.  E5-induced PDGF receptor activation involves complex formation between the E5 protein and the receptor via specific interactions between the transmembrane domains of these two proteins.  We are currently attempting to determine the molecular basis for the ability of the E5 protein to discriminate between the PDGF receptor and other transmembrane receptor tyrosine kinases, to gain insight into the rules that govern specific interactions between transmembrane helices.  We have also used genetic screens to identify artificial E5-like transmembrane proteins that can activate the PDGF receptor.  We are using related approaches to construct novel transmembrane proteins that activate or inhibit viral and cellular transmembrane proteins essential for virus growth or tumorigenesis, as novel anti-viral or anti-cancer agents.

We also study the role of the human papillomaviruses (HPV) in the pathogenesis of cervical carcinoma and are using this system to study the molecular basis for cellular senescence.  We showed that extinction of HPV oncogene expression in human cervical cancer cells results in the reactivation of the retinoblastoma and p53 tumor suppressor pathways, and in the rapid acquisition of a senescent state, an important tumor suppressor mechanism.  Our results imply that treatments that inhibit the expression or activity of viral proteins may be useful in treating HPV-associated cancers and that human cancer cells contain dormant tumor suppressor pathways.  We have used microarray based analysis to identify cellular mRNAs and microRNAs involved in senescence and have developed genetic screens to identify cellular genes required for virus infection or senescence.

Selected publications
Sweasy, J. B., Dalal, S., Starcevic, D., Sun, K. -W., Lai, C. -C., DiMaio, D. and Lang, T.  Expression of DNA polymerase ß cancer-associated variants in mouse cells results in cellular transformation.  Proc. Natl. Acad. Sci. (USA) 102, 14350-14355 (2005)

Lee, B. Y., Han, J. A., Lim, J. S., Morrone, A., Johung, K., Goodwin, E. C., Keijer, W., DiMaio, D. and Hwang, E. -S. Senescence-associated ß-galactosidase is lysosomal acid ß-galactosidase.  Aging Cell 5, 187-195 (2006)

Johung, K., Goodwin, E. and DiMaio, D. Human papillomavirus E7 repression in cervical cancinoma cells initiates a transcriptional cascade driven by the retinoblastoma family resulting in senescence.  J. Virol. 81, 2102-2116 (2007)

Horner, S. and DiMaio, D.  The DNA binding domain of a papillomavirus E2 protein programs a chimeric endonuclease to cleave integrated human papillomavirus DNA in HeLa cervical carcinoma cells.  J. Virol. 81, 6254-6264 (2007)

Ptacek, J. B., Edwards, A. P. B., Freeman-Cook, L. L. and DiMaio, D.  Hydrophobic contacts can mediate highly specific interactions between artificial transmembrane proteins and the transmembrane domain of the platelet-derived growth factor ß receptor.  Proc. Natl. Acad. Sci. (USA) 104, 11945-11950 (2007)