Research: Our lab is interested in the mechanisms by which human papillomaviruses
(HPVs) contribute to epithelial cancers. Most of our research has focused on
the HPVs that have a high risk of progression to cervical cancers, such as
HPV 16. We have sought to determine how the E6 and E7 oncoproteins disrupt
the cell cycle checkpoints that normally maintain genomic integrity, and how
E6/E7 facilitates the immortalization of primary human cells in culture.
Much of our current effort is directed towards understanding how and why E6
activates and increases expression of hTERT, the catalytic subunit of
telomerase. We are also studying the mechanisms by which other oncogenes,
such as c-MYC and Ha-RAS immortalize cells, and the tumor supressors that
constrain these activities.
In addition to mechanistic studies, we have had long-standing collaborations
with epidemiologists and clinicians to understand the natural history of
genital HPV infections, and the risk factors that cause only a small subset
of women infected with high risk HPVs to progress to cancer. To aid in these
studies we have developed serologic assays to detect and characterize
HPV-specific antibodies. The recent establishment of multiplex assays in our
lab is affording a more comprehensive assessment of the prevalence of HPV
infections.
More recently we have begun to study a different group of HPVs, known as the
genus beta HPVs. These beta HPVs commonly infect skin, and may play a role
in squamous cell skin cancers (SCSC). However unlike the genital HPVs, the
genus beta HPV E6/E7 proteins do not target p53 or Rb for degradation, nor
do the beta HPVs persist during tumor progression. We have developed methods
to detect beta HPV DNA and antibodies, are collaborating in studies to
define the role of beta HPV infection in SCSC in a cohort of organ
transplant recipients, and are studying the role of E6/E7 in blocking
UV-induced apoptosis, as well as other functions of E6/E7.
Selected Publications:
Carter, J.J., Wipf, G.C., Madeleine, M.M., Schwartz, S.M., Koutsky, L.A.,
Galloway, D.A. Identification of human papillomavirus type 16 L1 surface
loops required for neutralization by human sera. J. Virol. 80:4664-72. 2006.
Katzenellenbogen, R. A., Egelkrout, E. M., Vliet-Gregg, P., Gewin, L.C.,
Gafken, P.R., Galloway, D.A. NFX1-123 and poly(A) binding proteins
synergistically augment activation of telomerase in human papillomavirus
type 16 E6 expressing cells. J. Virol. 81:3786-3796. 2007.
Bedard, K.M., Underbrink, M.P., Howie, H.L., Galloway, D.A. The E6
oncoproteins from human betapapillomaviruses differentially activate
telomerase through an E6AP-dependent mechanism and prolong the lifespan of
primary keratinocytes. J. Virol. 82: 3894-3902. 2008.
Xu, M., Luo, W., Elzi, D., Grandori, C., Galloway, D.A. NFX1 represses
hTERT transcription by recruiting the Sin3A co-repressor. Mol. Cell. Bio.
28(15):4819-28. 2008.
Madeleine, M.M., Johnson, L.G., Smith, A.G., Hansen, J.A., Nisperos, B.B.,
Li, S., Zhao, L.P., Daling, J.R., Schwartz, S.M., Galloway, D.A.
Comprehensive analysis of HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 loci
and squamous cell cervical cancer risk. Cancer Res. 68:3532-3539. 2008.
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