Peter M. Howley, M.D.

Shattuck Professor of Pathological Anatomy
Head of the Department of Pathology

Harvard Medical School
New Research Building
77 Avenue Louis Pasteur
Tel: 617-432-2884
Fax: 617-432-2882
e-mail:phowley@hms.harvard.edu

The Howley laboratory studies the molecular biology of the papillomaviruses using the bovine papillomavirus (BPV) as well as the human papillomaviruses (HPVs). Projects in the laboratory involve the viral E1 and E2 proteins and their roles in the regulation of viral transcription, DNA replication and genome maintenance in dividing cells. We are conducting structure/function studies of the viral E1 and E2 proteins with the hope of developing inhibitors of their functions using proteomic and chemical genetic approaches. There are over 150 different HPVs, and some of them are associated with specific human cancers most notably human cervical cancer. We study the role of these HPVs in human neoplasia and the mechanisms by which they contribute to cellular transformation. The virus encodes two proteins, E6 and E7, that have oncogenic properties and that contribute directly to HPV associated carcinogenesis. A major focus of the laboratory is the study of E6 oncoprotein which has multiple functions, including the ability to functionally inactivate p53 by targeting its ubiquitylation and proteolysis. This process is mediated by a cellular protein, E6AP, that binds to E6 and functions as an E3 ubiquitin protein ligase in promoting the E6 dependent ubiquitylation of p53. Our work with the E6 mediated ubiquitylation of p53 has led us to ask fundamental questions about the ubiquitylation and protein degradation pathways. Our interests extend to other aspects of papillomavirus-host cell interactions, including how these viruses evade innate and adaptive host cell immune recognition. In this area, a major area of interest involves the Interferon Regulatory Factor 3 (IRF-3) which plays a critical role in the innate immune response to viral infections.

References:

1. Karpova, A.Y., Trost, M.,Murray, J.M., Cantley, L.C., and Howley, P.M. Interferon Regulatory Factor-3 is an in vivo target of DNA-PK. Proc. Nat. Acad. Sci. USA, 99:2818-2823, 2002.
2. Wells, S.I., Aronow, B.J., Wise, T.M., Williams, S., Couget, J. and Howley, P.M. Transcriptome signature of irreversible senescence in HPV positive cervical cancer cells. Proc. Nat. Acad. Sci. USA, 100:7093-7098, 2003.
3. Walters, K.J., Lech, P.J., Goh, A.M. Wang, Q., and Howley, P.M. Binding of the proteasomal subunit S5a opens the quartenary structure of the DNA repair protein hHR23a. Proc. Nat. Acad. Sci. USA, 100:12694-12699, 2003.
4. You, J. Croyle, J.L., Nishimura, A., Ozato, K., and Howley, P.M. Interaction of the bovine papillomavirus E2 protein with Brd4 tethers the viral DNA to host mitotic chromosomes. Cell, 117:349-360, 2004.
5. Kirshner, J.R., Karpova, A.Y., Kops, M., Howley, P.M. Identification of TRAIL as an IRF-3 transcriptional target. J. Virol. In press, July, 2005