Shattuck Professor of Pathological Anatomy
Chair, Department of Pathology
Harvard Medical School
NRB-950A
77 Ave Louis Pasteur
Boston, MA 02115
PH: 617-432-2884
FX: 617-432-2882
peter_howley@hms.harvard.edu

Assistant: Irina Goldina
Pathology@hms.harvard.edu
PH: 617-432-2884

Research Interests

Research in the Howley laboratory is focused on the molecular biology of the papillomaviruses and the role of these viruses in carcinogenesis. There is compelling evidence associating several specific types of the human papillomaviruses (HPVs) with human cervical cancer. These "high risk" HPV types such as HPV16 and HPV18 encode two oncoproteins, E6 and E7, which target the important cellular growth regulatory proteins p53 and pRb, respectively. We have previously shown that E6 promotes the ubiquitination 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 a cellular protein, called the E6 Associated Protein (E6AP), that binds to E6 and participates directly in its ubiquitination. 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.

We study both the bovine papillomavirus (BPV), which has served as the prototype for studies of the molecular biology of the papillomaviruses, as well as the HPVs that have been associated directly with human cancer. One area of research in the laboratory has focused on the E1 and E2 regulatory genes encoded by the papillomaviruses. E1 and E2 together are required for the initiation of viral DNA replication and E2 has additional roles controlling viral transcription. Structure/function studies of the E1 and E2 regulatory proteins are being pursued. Proteomic studies are also being conducted to determine cellular interacting proteins key for viral host cell interactions.

The laboratory has had a particular interest in other functions of HPV E6 proteins. In addition to promoting the ubiquitination of p53, E6 has other functions in cellular transformation and pathogenesis through its ability to interact with specific cellular proteins. We are also studying additional mechanisms by which E6 may perturb normal cell functions and have identified the focal adhesion protein paxillin and the interferon response factor IRF3 as targets of E6.

Publications

Kleijnen, M. F., Shih, A. H., Zhou, P., Kumar, S., Soccio, R.E., Kedersha, N.L., Gill, G., and Howley, P.M. 2000 The hPLIC proteins may provide a link between the ubiquitination machinery and the proteasome. Molecular Cell. 6:409-419.

Karpova, A.Y., Trost, M.,Murray, J.M., Cantley, L.C., and Howley, P.M. (2002) Interferon Regulatory Factor-3 is an in vivo target of DNA-PK. Proc. Nat. Acad. Sci. USA, 99:2818-2823.

Wells, S.I., Aronow, B.J., Wise, T.M., Williams, S., Couget, J. and Howley, P.M. (2003) Transcriptome signature of irreversible senescence in HPV positive cervical cancer cells. Proc. Nat. Acad. Sci. USA, in press.