Peter M. Howley
Harvard University
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Primary Section: 44, Microbial Biology Secondary Section: 41, Medical Genetics, Hematology, and Oncology Membership Type:
Member
(elected 1993)
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Research Interests
As a virologist and pathologist, I have studied the papillomaviruses and the mechanisms by which they participate in carcinogenesis. Using molecular techniques, my laboratory has analyzed the functions of viral E6 and E7 genes expressed in HPV positive cancers and of E2 that regulates expression of the viral oncoproteins. We found that E6 and E7 target p53 and pRB respectively, and inactivate their tumor suppressor functions. E6 binds p53 and promotes its ubiquitination and subsequent proteolysis. By identifying the cellular factors involved in the E6/p53 ubiquitination pathway, we discovered a new family of cellular proteins that are ubiquitin-protein ligases that function directly in the recognition of substrates. The papillomavirus E2 proteins are important viral regulatory proteins. In the HPVs associated with cancers, E2 is a negative regulator of viral oncoprotein expression. Progression of benign HPV positive precursor lesions to cancers is usually correlated with a loss of E2 expression. Reintroduction of E2 back into these cancers suppresses cell growth. We are now analyzing the mechanisms by which E2 in inhibits cellular proliferation. A more thorough understanding of these mechanisms could lead to the development of new ways to treat or prevent cancer.
