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DANIEL DIMAIO

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

The E5 oncoprotein of bovine papillomavirus is an extremely short transmembrane (TM) protein that transforms cells by activating the platelet-derived growth factor ß receptor via TM interactions. This discovery identified a novel mechanism of oncogene action and demonstrated that receptor tyrosine kinases can be activated by small proteins unrelated to their normal ligands. We are currently studying the molecular basis for the action of the E5 protein, to gain insight into the rules that govern specific interactions between TM helices. We have also used genetic screens to identify biologically active, artificial E5-like TM proteins. In addition to artificial proteins that can activate the PDGF receptor, we have also isolated proteins that can activate the human erythropoietin receptor to drive the formation of red blood cells and inhibit the expression of CCR5 and block infection by HIV.

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 are analyzing signaling pathways that mediate senescence with a focus on novel microRNA regulatory circuits.
Finally, we are using genome-wide RNA interference techniques to identify and characterize cellular genes required for infection by tumor viruses. We have identified numerous cellular genes required for exit of polyomaviruses from the endoplasmic reticulum during cell entry or for the entry of the HPV into the nucleus. We are studying the roles these genes play in virus infection and normal cellular physiology.

Recent publications:

Talbert-Slagle, K., Marlatt, S., Barrea, F.N., Oates, J., Gerstein, M., Engelman, D., Dixon, A., and DiMaio, D. (2009) Artificial transmembrane oncoproteins smaller than the bovine papillomavirus E5 protein redefine the sequence requirements for activation of the PDGF b receptor. J. Virol. 83: 9773-85.

Cammett, T.J., Jun, S.J., Cohen, E.B., Barrea, F.N., Engelman, D., and DiMaio, D. (2010) Construction and genetic selection of small transmembrane proteins that activate the human erythropoietin receptor. Proc. Natl. Acad. Sci. (USA) 107: 3447-52.

Martinez, I., Cazella, D., Almstead, L., Steitz. J., and DiMaio, D. (2011) miR-29 and miR-30 regulate B-Myb during cellular senescence. Proc. Natl. Acad. Sci. 108:522-7. PMID: 21187425.

Goodwin, E.C., Lipovsky, A., Inoue, T., Magaldi, T., Yates, K.E., Paton, A., Paton, J., Atwood, W., Tsai, B., and DiMaio, D. (2011) BiP and multiple DNAJ molecular chaperones in the endo-plasmic reticulum are required for efficient SV40 infection. mBio 2: doi:10.1128/mBio.00101-11.

Last updated 8/9/11 myc