Peter Howley
Professor and Chair, Department of Pathology
Harvard Medical School
New Research Building, Room 950
77 Avenue Louis Pasteur
Boston, MA 02115
Tel: (617) 432-2884
Fax: (617) 432-2882
Email: peter_howley@hms.harvard.edu
5 postdoctoral fellows, 2 graduate students
Research in the Howley laboratory is focused on the molecular biology of the papillomaviruses and the role of these viruses in carcinogenesis. Several specific types of the human papillomaviruses (HPVs) are associated with human cervical cancer. The "high risk" HPVs encode two oncoproteins, E6 and E7, which target the tumor suppressor gene proteins p53 and pRB, respectively. We have previously shown that E6 promotes the ubiquitylation and degradation of p53, and are now interested in the general question of how proteins are recognized within cell by the ubiquitin proteolytic machinery. The E6 promoted ubiquitylation of p53 is mediated by the cellular protein E6AP that complexes with E6 to directly target p53 for ubiquitylation. We are interested in how E6AP is regulated and the identification of additional cellular proteins that E6AP targets in cells, either in the presence of or absence of the viral E6 protein.
One area of research in the laboratory has focused on the E2 regulatory proteins encoded by the papillomaviruses. The E2 protein regulates expression of the viral E6 and E7 oncoproteins, has an auxiliary role in viral DNA replication and is required for viral genome maintenance in persistent infections. We identified the bromodomain protein Brd4 as a key cellular binding partner of E2 that mediates a number of these important functions. Projects in the laboratory involving the viral E2 protein employ proteomic approaches to identify cellular proteins and pathways involved in HPV virus host cell interactions. We also employ siRNA and shRNA screens to further characterize and explore these 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. An additional area of study in the laboratory involves the study of the BPV E7 protein and its interacting protein UBR4. Rotation projects are available in each of these areas.
References:
- 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.
- DeMasi, J., Huh, K.-W., Nakatani, Y., Münger, K., and Howley, P.M., Bovine papillomavirus E7 transformation function
- correlates with cellular p600 protein binding. Proc. Nat. Acad. Sci. USA, 102:11486-11491, 2005.
- Schweiger, M.-R., Ottinger, M., You, J., and Howley, P.M. Brd4 independent transcriptional repression function of the papillomavirus E2 proteins. J. Virol. 81:9612-9622, 2007.
- Zheng, G., Schweiger, M.-R., Martinez-Noel, G., Zhang, L., Smith, J.A., Harper, J.W., and Howley, P.M. Brd4 regulation of papillomavirus E2 stability. J. Virol. In press, 2009.
- Vos, R.M., Altreuter, J., White, E.A. and Howley, P.M., The ubiquitin specific protease USP15 regulates human papillomavirus 16 E6 protein stability. J. Virol. In press, 2009.
BBS webpage updated 12/02/2009