Laimonis A. Laimins, PhD Professor Microbiology-Immunology Human papillomaviruses and cervical cancer Curricula: Cancer Biology Immunology and Microbial Pathogenesis Molecular Biology and Genetics E-mail:   l-laimins@northwestern.edu

My laboratory studies the molecular biology of human papillomaviruses (HPV) and their association with cervical cancer. Our efforts are divided into two main categories: 1) examination of how the viral oncoproteins, E6 and E7, contribute to the development of malignancy and 2) studies on the mechanisms controlling the viral life cycle in differentiating epithelia. Over seventy distinct types of human papillomavirus have been identified and approximately one-third specifically target squamous epithelial cells in the genital tract. Of these genital papillomaviruses, a subset including types 16,18 and 31, have been shown to be the etiological agents of most cervical cancers.

One of our goals is to understand why infection by specific HPV types contributes to the development of malignancy. For these studies we have examined the interaction of the oncoproteins, E6 and E7 with cellular proteins. In particular, E6 binds the p53 protein and facilitates its degradation by a ubiquitin-mediated pathway. E7 binds the retinoblastoma gene product and alters its cell cycle regulatory proteins. The interactions of the E6 and E7 proteins with these cellular proteins are being examined at both the biochemical and genetic level.

Our second major area of study involves the examination of the papillomavirus life cycle. The production of papillomaviruses is closely linked to epithelial differentiation and progeny virus are replicated in terminally differentiated epithelial cells. We have used organotypic tissue culture systems to faithfully reproduce the differentiation program of epithelial cells in the laboratory. Using this system, the viral life cycle has been duplicated and we are currently studying the mechanisms that regulate viral DNA replication and gene expression. These studies should provide insight into viral pathogenesis as well as on the mechanisms regulating epithelial differentiation.

Publications:

Thomas, J.T., Oh, S.T., Terhune, S. and. Laimins, L.A. Cellular changes induced by low risk human papillomavirus type 11 in keratinocytes that stably maintain viral episomes. J. Virol. 75:7564-7571. 2001

Terhune, S., Hubert, W., Thomas, J. T. & Laimins, L.A. Early HPV 31 polyadenylation signals negatively regulate capsid gene expression. J. Virol  75:8147-8157. 2001

Oh, S., Kyo, S. and Laimins, L.A. Telomerase activation by HPV-16 E6: induction of hTERT expression through Myc and GC-rich Sp1 binding sites. J. Virol. 2001;75 5559-5566. 2001.

Hubert, W. and Laimins, L.A. HPV31 establishment and maintenance are regulated differentially by the viral replication factors E1 and E2 and E6-internal mRNA splicing. J. Virol. 2002;76 2263-2273

del Mar Pena, L. and Laimins, L.A. Differentiation-dependent chromatin rearrangement coincides with activation of HPV 31 late gene expression.J. Virol. 75:10005-10013. 2001.

Chang, Y. E., del Mar Pena, L. , Sen, G., Park, J. and Laimins, L. A. The Long Term Effect of Interferon on Keratinocytes That Maintain Human papillomavirus Type 31.  J. Virol. 2002;76 8864-8874

Fehrmann, F., Klumpp, D., Laimins, L.A. HPV31 E5 Protein Supports Cell Cycle Progression and Activates Late Viral functions upon Epithelial Differentiation. J. Virol 77: 2819-2831. 2003

Fehrmann, F. and Laimins, L. A Human papillomaviruses: targeting of differentiating epithelia for malignant conversion. Oncogene 22:5201-5207.2003.