Papillomaviruses (PVs) infect the epithelial of a wide variety of animals and man where they generally induce benign proliferation at the site of infection. However, there is a strong association between malignant progression of human genital lesions and certain HPV types, most frequently HPV16. Our previous work has established that PVs encode three transforming genes: E5, E6 and E7. Others have shown that E6 binds the tumor suppressor protein p53 and induce its degradation in vitro. We have now determined that E6 decreases the in vivo half-life of p53 in human keratinocytes that express HPV16 E6 at least 8 fold. To examine the relevance of p53 inactivation to the biological activities of E6, we examined the ability of mutant p53, which specifically inactivates wild type p53, to functionally substitute for E6. It was able to substitute in cooperating with E7 to immortalize normal human keratinocytes but not to transform NIH3T3 cells or trans-activate the adenovirus E1a promoter, indicating that E6 has both p53 dependent and independent activities. Our previous studies have shown that BPV E5 induces the ligand independent activation of growth factor receptors. We have now constructed a series of PDGF and EGF receptor chimeras to examine the receptor domains responsible for this activation. Our results indicate that the transmembrane domain of PDGFR is primarily responsible for its responsiveness to E5 while the intracellular domain of EGFR is required for its activation by E5. These results strongly suggest that E5 activates the two receptors by different mechanisms. We have begun to identify and characterize a cellular protein that specifically binds E5. Biochemical analysis and partial protein sequencing indicate that it is a new member of a family of proteins involved in intracellular protein trafficking. Analysis of the structural and immunogenic features of PVs has been hampered by the inability to propagate the viruses in cultured cells. To partially overcome this handicap, we have expressed the L1 major capsid proteins of BPV1 and HPV16 via baculovirus vectors. The L1 proteins were expressed at high levels and assembled into PV virion-like structures. The self assembled BPV L1 resembled intact virions in being able to induce high titer neutralizing antiserum. These results indicate that L1 has the intrinsic capacity to assemble into empty capsid-like structures whose immunogenicity is similar to infectious virions. This type of L1 preparation might be considered as a candidate for a vaccine to prevent PV infection.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Intramural Research (Z01)
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Division of Cancer Biology and Diagnosis
United States
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