The human papillomaviruses have been associated with several genital tract cancers. Over 70 different papillomaviruses (HPVs) have now been identified. Approximately 25 of these are associated with genital tract lesions. The HPVs that affect the anogenital area can be separated on the basis of their clinical associations into two distinct groups. One group, including HPV-6 and HPV-11, is generally associated with benign anogenital warts that infrequently progress to cancer and is referred to as """"""""low risk"""""""" viruses. The """"""""high risk"""""""" group, including HPV-16 and HPV- 18, is associated with intraepithelial neoplastic lesions that are at high risk for malignant progression. The laboratory has been studying the role that HPVs may play in the progression of a benign lesion to a malignant lesion. In HPV-16 and HPV-18 associated human cancers, the viral DNA is often integrated into the host genome in a manner that leads to the disruption of the E1 and E2 genes, suggesting that the disruption of these regulatory genes plays an important role in carcinogenic progression. The E1 and E2 proteins are DNA binding proteins which are involved in DNA replication and regulation of transcription. Mutations that disrupt either the E1 or E2 genes of HPV-16 dramatically increase viral immortalization capacity. The mechanism of suppression of immortalization by the E1 and E2 proteins is currently a major emphasis of the laboratory. The E6 and E7 proteins of the """"""""high risk"""""""" HPVs are required for immortalization of primary human keratinocytes and have been shown to interact with the tumor suppressor proteins, p53 and pRB, respectively. The E6 protein targets p53 for degradation through the ubiquitination pathway. E6 abrogates the normal transactivation properties of p53. Transactivation of cellular proteins by p53 and modulation of this transactivation by E6 is also a major focus of the laboratory.
