Bettina Ehret ( 08 / 88-, leave of absence )

Secretaries: Angela Cozzolino Cascone Marie Leroy-Schell The research of the Division Virus-Host-Interactions is focused on basic and applied aspects of viral carcinogenesis, with an emphasis on malignancies associated with human papillomaviruses (HPV) or hepatitis B virus (HBV). Specifically, the molecular mechanisms of virus-induced cell transformation, as well as the interplay between viral and cellular factors are being studied. In addition, our understanding of these events at the molecular level has led us to the development of novel strategies for diagnosis and therapy. In basic research, a novel candidate tumor suppressor gene, namely APM1, has been identified and characterized; it encodes a putative transcription factor with BTB and zinc finger domains. The APM1 gene has been found to be affected by HPV DNA integration in the cervical carcinoma cell line ME180. In other human tumor cell lines, APM1 mRNA levels differ extensively thereby suggesting that alterations in APM1 expression might contribute to carcinogenesis. APM1 gene expression seems to be regulated in a very complex manner, including multiple promoters, GC-rich 5’UTR exons and gene silencing by DNA methylation. Future work will be directed towards identifying the role of APM1 in human carcinogenesis. Another research interest has been the analysis of the HPV E6 oncoprotein/p53 interaction. We have shown that HPV-positive cancer cells can reactivate dormant p53-associated pathways, a fact that makes inhibition of the p53 antagonist HPV E6 an interesting therapeutic target, with the reactivation of the anti-oncogenic activities of p53 as a result. For HBV, a new type of truncated transcripts terminating at a cryptic polyadenylation signal has been studied. The conditions for the use of this polyadenylation signal and the potential of truncated mRNA to direct the synthesis of a putative truncated HBx protein have been investigated. The latter was shown to represent a seperate functional HBx entity. Investigations on early steps in hepatitis B virus replication and the structure of the viral mini-chromosome support the concept on an impact of the HBV core protein on the nuclear targeting of the HBV genome. Truncated HBV transcripts were established as markers of a chronic HBV infection, their fraction increasing with its duration. They provide a key to the recognition of non-replicative, occult stages of the HBV infection. Since they are also found as circulating RNA in blood, they may provide a new basis for non-invasive diagnosis. Finally, a version of the “Peptide Aptamer System” has been developed in the department. This approach allows for the identification of peptides which can act as specific inhibitors of a given target protein, at the intracellular level. We have shown that peptide aptamers targeting the HPV16 E6 oncoprotein resulted in the apoptotic elimination of HPV-positive cancer cells. These aptamers form a basis for the development of new therapeutic strategies against HPV-associated dysplasias and cancers. Division Virus Host Interactions (F0600)