Paul F. Lambert, Ph.D.
Professor of
Oncology
B.S., 1979, Biochemistry, University of
Massachusetts, Amherst
Ph.D., 1985, Biochemistry, University of
Wisconsin-Madison
Postdoctoral research: Laboratory of
Peter Howley, National Cancer Institute
Office: 220A McArdle
Laboratory
Telephone: Office - (608) 262-8533; Lab -
(608) 262-6407
Email: lambert@oncology.wisc.edu
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Research Interests: Molecular genetics of papillomaviruses
Research Description: Our research focuses on understanding the biology of human papillomaviruses (HPV) that are implicated in human cancer. A subset of HPVs, most common amongst these HPV16, are now accepted to be the main cause of cervical cancer in women, with greater than 99% of these cancers harboring HPV DNA. In cervical cancers, two viral genes E6 and E7 are selectively expressed. To investigate the role of E6 and E7 in cancer, we have generated transgenic mice in which we targeted expression of HPV16 E6 and E7 to stratified squamous epithelia, the normal tissue site of infection from which cancers arise in humans. These mice are at increased risk of cancers in the skin and the cervix. Using these mice we are investigating the mechanisms of action of E6 and E7, and have found that their interaction with cellular tumor suppressors as well as other cellular factors contribute to their biological activities in vivo. Recently we have also begun studies of a third HPV oncogene, E5, which, while not always expressed in cervical cancers, likely contributes to the progressive disease that leads to the formation of these and other HPV-associated cancers. Recently constructed transgenic mouse models for studying this viral oncogene are providing exciting new insights into its oncogenic properties in vivo.
A second focus of our laboratory is the study of the HPV
life cycle. The viral life cycle is intricately tied to the
terminal differentiation of the host epithelium infected by
the virus. Using an organotypic culturing technique that
effectively leads to the formation of synthetic skin in the
laboratory, we are investigating the roles of viral and
cellular genes in the papillomavirus life cycle. We
discovered that E7, one of the two viral genes implicated
in cervical cancer, plays a critical role in the
reprogramming terminally differentiating epithelial cells
to support the amplification of the viral genome, a process
that is highly reliant upon the cellular DNA synthetic
machinery. This machinery is normally inactive in
terminally differentiating cells. We also discovered that
E5, another viral oncogene, also contributes to this
reprogramming step. Ongoing studies are directed at
understanding the role of other viral genes in the life
cycle. Recently we discovered that HPV DNA genomes can
replicate in yeast and this now provides us a valuable
surrogate host in which to identify cellular factors that
can contribute to viral DNA replication. Finally, we are
interested in how the host modulates the virus. We
discovered that methylation of the viral genome by cellular
DNA methylases is a dynamic process that can modulate the
activity of a viral transcription factor, E2, and likely
plays a critical role in modulating levels of viral gene
expression during the viral life cycle. These studies
provide a foundation for our future interests in
understanding the papillomaviral life cycle.
Selected recent publications
Bonilla-Delgado, J., Bulut, G., Liu, X., Cortés-Malagón, E. M., Schlegel, R., Flores-Maldonado, C., Contreras, R. G., Chung, S.-H., Lambert, P. F., Üren, A., and Gariglio, P. The E6 Oncoprotein from HPV16 Enhances the Canonical Wnt/β-Catenin Pathway in Skin Epidermis in Vivo. Mol. Cancer Res., 10: 250-258, 2012.
Huang, H.-S., Pyeon, D., Pearce, S. M., Lank, S. M., Griffin, L. M., Ahlquist, P., and Lambert, P. F. Novel Antivirals Inhibit Early Steps in HPV Infection. Antiviral Res., 93: 280-287, 2012.
Shin, M.-K., Pitot, H. C., and Lambert, P. F. Pocket Proteins Suppress Head and Neck Cancer. Cancer Res., 72: 1280-1289, 2012.
Wen, Z., Pyeon, D., Wang, Y., Lambert, P., Xu, W., and Ahlquist, P. Orphan Nuclear Receptor PNR/NR2E3 Stimulates p53 Functions by Enhancing p53 Acetylation. Mol. Cell. Biol., 32: 26-35, 2012.
Al-Dhaheri, M., Wu, J., Skliris, G. P., Li, J., Higashimato, K., Wang, Y., White, K. P., Lambert, P., Zhu, Y., Murphy, L., and Xu, W. CARM1 Is an Important Determinant of ERα-Dependent Breast Cancer Cell Differentiation and Proliferation in Breast Cancer Cells. Cancer Res., 71: 2118-2128, 2011.
Thomas, M. K., Pitot, H. C., Liem, A., and Lambert, P. F. Dominant Role of HPV16 E7 in Anal Carcinogenesis. Virology, 421: 114-118, 2011.
Zehbe, I., Lichtig, H., Westerback, A., Lambert, P. F., Tommasino, M., and Sherman, L. Rare Human Papillomavirus 16 E6 Variants Reveal Significant Oncogenic Potential. Mol. Cancer, 10:77, 2011.
Chung, S.-H., Franceschi, S., and Lambert, P. F. Estrogen and ERα: Culprits in Cervical Cancer? Trends Endocrinol. Metab., 21: 504-511, 2010.
DeCarlo, C. A., Severini, A., Edler, L., Escott, N. G., Lambert, P. F., Ulanova, M., and Zehbe, I. IFN-κ, a Novel Type I IFN, Is Undetectable in HPV-Positive Human Cervical Keratinocytes. Lab. Invest., 90: 1482-1491, 2010.
Huang, H.-S., Buck, C. B., and Lambert, P. F. Inhibition of Gamma Secretase Blocks HPV Infection. Virology, 407: 391-396, 2010.