Genomic instability induced by the HPV-16 E7 oncoprotein

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

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Abstract

DESCRIPTION (provided by applicant): Cancer of the uterine cervix is intimately associated with an infection by high-risk human papillomavirus (HPV) types such as HPV-16 or HPV-18. In cervical carcinomas, the two viral oncoproteins E6 and E7 are consistently overexpressed and these tumors are frequently genomically unstable and show centrosome abnormalities. Centrosomes are the major microtubule organizing centers in animal and human cells and have been implicated in multipolar mitoses, chromosome missegregation and aneuploidy, the most common form of genomic instability in cancer. Although centrosome anomalies can be detected in virtually all malignant tumors, the underlying molecular mechanisms are largely unknown. We discovered that HPV-16 E7 rapidly uncouples centrosome duplication from the cell division cycle in normal human cells and stimulates multipolar mitoses and aneuploidy. Previous results suggest that HPV-16 E7 disrupts centrosome duplication through inactivation of pRB family members in combination with additional cellular targets. Moreover, this activity of the E7 oncoprotein requires ubiquitin-proteasome-mediated proteolysis. In addition to centrosome aberrations, we found that HPV-16 E7 expression causes DMA damage. The aims of this application therefore are: 1) To determine the cellular targets through which HPV-16 E7 induces centrosome overduplication and aberrant licensing of maternal centrioles; 2) To investigate how HPV-16 E7 interferes with proteolytic activity at the centrosome in order to promote abnormal centrosome duplication; and 3) To establish a causative role of HPV-16 E7-induced centrosome anomalies in the development aneuploidy and to explore whether DNA damage in HPV-16 E7-expressing cells is a cause or consequence of aberrant centrosome duplication. Since the HPV E7 oncoprotein subverts cellular targets that are frequently altered in genomically unstable non-virus-associated tumors, our research will help to understand the molecular basis of genomic instability in cancer in general.