This program project has two objectives: to use molecular biology and genetics to elucidate the life cycles of and transformation by human tumor viruses and to translate this understanding into the identification of targets for specific anti-viral, anti-tumor therapies. This program includes six investigators who share these research goals in studying four human tumor viruses that together account for the majority of human cancers caused by viruses. Our program has evolved to foster two or more investigators working together on individual projects and to cross-fertilize these projects by multiple investigators working on pairs of projects. This evolution has been made possible by collaborations that have developed among current investigators and with new investigators. Dr. Kenney has moved from the Lineberger Cancer Center and joined our team to understand Epstein-Barr Virus's (EBV) pathogenicity through her fundamental research and her clinical expertise. Dr. Janet Mertz has identified and characterized cellular factors that regulate expression of viral genes and is collaborating with Dr. Kenney to define the mechanisms that control the switch from EBV's latent to lytic cycle. A tenet of their work is that inducing EBV's lytic cycle efficiently in tumors would be therapeutically beneficial. Drs. Kenney and Mertz are collaborating with Dr. Sugden to uncover EBV's functions necessary to sustain its lymphomas. They are also examining virally associated pathways and their inhibitors, some now used in clinical trials, as targets for developing therapies and as possible therapies now. Dr. Sugden is collaborating with Dr. Lambert to study the plasmid replication of EBV, Kaposi's Sarcoma Herpes Virus (KSHV), and human papillomavirus (HPV) type 16 both to understand them and ultimately to identify features that render them vulnerable to inhibition. Dr. Lambert is collaborating with Dr. Ahlquist to study HPV16 in transgenic mouse models and human cancer patients to identify the mechanisms of HPV infection, oncogene action, and tumor progression. Dr. Ahlquist is collaborating with Dr. Loeb to combine findings of their large-scale cell screens and robust cellular models to dissect the viral and cellular contributions to the replication of human hepatitis B virus (HBV). All of these collaborations will illuminate how these human tumor viruses replicate. All will identify and characterize steps in viral life cycles, viral oncogenic functions, and cellular cofactors that are targets for therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA022443-35
Application #
8254300
Study Section
Special Emphasis Panel (ZCA1-GRB-S (J1))
Program Officer
Daschner, Phillip J
Project Start
1997-02-01
Project End
2013-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
35
Fiscal Year
2012
Total Cost
$1,850,672
Indirect Cost
$591,558
Name
University of Wisconsin Madison
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Park, Jung Wook; Nickel, Kwangok P; Torres, Alexandra D et al. (2014) Human papillomavirus type 16 E7 oncoprotein causes a delay in repair of DNA damage. Radiother Oncol 113:337-44
Wang, Lu; Zhao, Zibo; Meyer, Mark B et al. (2014) CARM1 methylates chromatin remodeling factor BAF155 to enhance tumor progression and metastasis. Cancer Cell 25:21-36
Kuzembayeva, Malika; Hayes, Mitchell; Sugden, Bill (2014) Multiple functions are mediated by the miRNAs of Epstein-Barr virus. Curr Opin Virol 7:61-5
Wang, Joseph Che-Yen; Nickens, David G; Lentz, Thomas B et al. (2014) Encapsidated hepatitis B virus reverse transcriptase is poised on an ordered RNA lattice. Proc Natl Acad Sci U S A 111:11329-34
Stein, Andrew P; Saha, Sandeep; Yu, Menggang et al. (2014) Prevalence of human papillomavirus in oropharyngeal squamous cell carcinoma in the United States across time. Chem Res Toxicol 27:462-9
Iempridee, Tawin; Reusch, Jessica A; Riching, Andrew et al. (2014) Epstein-Barr virus utilizes Ikaros in regulating its latent-lytic switch in B cells. J Virol 88:4811-27
Park, J W; Shin, M-K; Lambert, P F (2014) High incidence of female reproductive tract cancers in FA-deficient HPV16-transgenic mice correlates with E7's induction of DNA damage response, an activity mediated by E7's inactivation of pocket proteins. Oncogene 33:3383-91
Shrestha, Prabha; Sugden, Bill (2014) Identification of properties of the Kaposi's sarcoma-associated herpesvirus latent origin of replication that are essential for the efficient establishment and maintenance of intact plasmids. J Virol 88:8490-503
Vereide, D T; Seto, E; Chiu, Y-F et al. (2014) Epstein-Barr virus maintains lymphomas via its miRNAs. Oncogene 33:1258-64
Son, Jieun; Park, Jung Wook; Lambert, Paul F et al. (2014) Requirement of estrogen receptor alpha DNA-binding domain for HPV oncogene-induced cervical carcinogenesis in mice. Carcinogenesis 35:489-96

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