Alison McBride, Ph.D.

Chief, DNA Tumor Virus Section

Description of Research Program

The papillomaviruses (Los Alamos National Laboratory Bioscience Division website) are small DNA viruses that induce persistent benign epithelial lesions. In some cases these lesions can progress to malignant carcinomas, the most notable of which is cervical cancer. The viral E1 and E2 genes regulate viral transcription, replication, and genome segregation. Our objective has been to understand the mechanisms by which they control the viral life cycle.

My laboratory studies the ways in which the E2 proteins regulate viral gene expression and how the E1 and E2 proteins act in concert to replicate papillomavirus DNA. These studies have provided detailed information about how the proteins interact with the viral DNA and with each other and how their activities are regulated within infected cells.

The E2 transactivator protein is required for viral transcriptional regulation, DNA replication, and stable episomal maintenance of viral genomes. We have shown that papillomavirus genomes are tethered to mitotic chromosomes by the E2 transactivator protein. This ensures that viral genomes remain in the nucleus and are segregated to daughter cells in approximately equal numbers. The figure below shows a mitotic cell with spindle (red), chromosomes (blue), and E2 protein (green).

Papillomaviruses induce proliferative epithelial lesions and can only undergo vegetative replication in terminally differentiated keratinocytes. This has hampered the study of the complete viral life cycle because of the difficulties in generating a differentiated stratified epithelium in tissue culture. Using a combination of organotypic raft cultures and xenografts on nude mice, we have developed a system in which we can generate fully differentiated epithelium in which papillomaviruses can replicate and produce infectious viral particles. This system is being used for a genetic analysis of the roles of the E1 and E2 viral gene products in the complete viral life cycle.

In the majority of carcinomas, papillomavirus genomes are found integrated into cellular chromosomes such that the E1 and/or E2 genes are disrupted. This has led to the hypothesis that disruption of the E1 and E2 regulatory functions is a critical step in progression to a carcinoma.

We are currently studying the role of the E1 and E2 regulatory functions in keratinocyte growth and differentiation. Because the E1 and E2 proteins have both positive and negative effects on the viral life cycle and on malignant progression, a detailed understanding of their regulatory mechanisms is crucial for the design of antiviral strategies.

Research Group Members

Jonathan Spindler, Biologist; Emiko Soeda, Postdoctoral Fellow; Jaquelline Oliveira, Postdoctoral Fellow; Maria McPhillips, Postdoctoral Fellow; Juan Cardenas, Postbaccalaureate Fellow; Shawna Reed, Postbaccalaureate Fellow; Paulo Ferreira, Visiting Scientist

Selected Publications

(View list in PubMed.)

McPhillips MG, Ozato K, McBride AA. Interaction of BPV E2 protein with Brd4 stabilizes its association with chromatin. J Virol. 2005 Jul;79(14):8920-32.

Brannon AR, Maresca JA, Boeke JD, Basrai MA, McBride AA. Reconstitution of papillomavirus E2-mediated plasmid maintenance in Saccharomyces cerevisiae by the Brd4 bromodomain protein. Proc Natl Acad Sci USA. 2005 Feb 22;102(8):2998-3003.

Baxter MK, McBride AA. An acidic amphipathic helix in the Bovine Papillomavirus E2 protein is critical for DNA replication and interaction with the E1 protein. Virology. 2005 Feb 5;332(1):78-88.

Baxter MK, McPhillips MG, Ozato K, McBride AA. The mitotic chromosome binding activity of the papillomavirus E2 protein correlates with interaction with the cellular chromosomal protein, Brd4. J Virol. 2005 Apr;79(8):4806-18.

Zheng PS, Brokaw J, McBride AA. Conditional mutations in the mitotic chromosome binding function of the bovine papillomavirus type 1 E2 protein. J Virol. 2005 Feb;79(3):1500-9.

McBride AA, McPhillips MG, Oliveira JG. Brd4: tethering, segregation and beyond. Trends Microbiol. 2004 Dec;12(12):527-9.

back to top