This is an application for a 5-year extension of my MERIT award that is currently in its fourth year (2007- 2011). The long-term goal of this grant is to investigate the mechanisms that regulate the productive life cycle of human papillomaviruses (HPV) with a focus on the action of the early viral proteins, E5, E1 '^E4, E7 and E6. Understanding the pathways that are targeted by these factors will help elucidate how the productive life cycle is regulated and will provide significant insights into what controls progression to malignancy. In the past four years, we have published or have in press 10 peer-reviewed manuscripts that were supported by this grant along with three review articles. Our studies have shown that E5 plays an important role in maintaining cell proliferative capacity upon differentiation as well as in modulating trafficking of proteins through the ER due to interactions with cellular proteins Bap31 and A4. The E1'^E4 proteins of high-risk HPVs were also shown to play important roles in the late phase of the life cycle. Additional work indicates that E6 activates low levels of caspases upon differentiation along with the ATM-DNA damage response and that these activities are important for productive HPV replication. We have further observed that E6 suppresses STAT-1 expression and this is necessary for stable maintenance of HPV episomes as well as amplification. Additional important activities identified for E6 include blocking of p300 acetylation of p53 and activation of p63 upon differentiation. E7 was shown to enhance HIF-1 activity by modulating HDAC interactions along with playing an essential role in the life cycle. In this application, I propose to continue these studies in the next funding period addressing similar aims.
The specific aims of the MERIT award are: 1). How do the high-risk E5 proteins activate the differentiation-dependent late phase of the HPV life cycle? 2). Which activities of E1'^E4 proteins are important for the late phase of the HPV life cycle? 3). How does E6 facilitate maintenance of episomes in undifferentiated cells? What activities does E6 control in differentiated cells? How does E7 complement the activities of E6?

Public Health Relevance

Cervical cancer is a worldwide leading cause of death of women by cancer. The causative agents of over 99% of these malignancies are high-risk human papillomaviruses. This study seeks to investigate the mechanisms regulating the productive life cycle of human papillomaviruses and this will provide insights into how, in some cases. Infections result in malignancies.

Agency
National Institute of Health (NIH)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37CA074202-18
Application #
8710013
Study Section
No Study Section (in-house review) (NSS)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
Project End
Budget Start
Budget End
Support Year
18
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Chicago
State
IL
Country
United States
Zip Code
60611
Kotnik Halavaty, Katarina; Regan, Jennifer; Mehta, Kavi et al. (2014) Human papillomavirus E5 oncoproteins bind the A4 endoplasmic reticulum protein to regulate proliferative ability upon differentiation. Virology 452-453:223-30
Hong, Shiyuan; Laimins, Laimonis A (2013) The JAK-STAT transcriptional regulator, STAT-5, activates the ATM DNA damage pathway to induce HPV 31 genome amplification upon epithelial differentiation. PLoS Pathog 9:e1003295
Bodily, Jason M; Mehta, Kavi P M; Laimins, Laimonis A (2011) Human papillomavirus E7 enhances hypoxia-inducible factor 1-mediated transcription by inhibiting binding of histone deacetylases. Cancer Res 71:1187-95
Knight, Gillian L; Pugh, Alice G; Yates, Emma et al. (2011) A cyclin-binding motif in human papillomavirus type 18 (HPV18) E1^E4 is necessary for association with CDK-cyclin complexes and G2/M cell cycle arrest of keratinocytes, but is not required for differentiation-dependent viral genome amplification or L1 cap Virology 412:196-210
Mighty, Kristen K; Laimins, Laimonis A (2011) p63 is necessary for the activation of human papillomavirus late viral functions upon epithelial differentiation. J Virol 85:8863-9
Bodily, Jason; Laimins, Laimonis A (2011) Persistence of human papillomavirus infection: keys to malignant progression. Trends Microbiol 19:33-9
Beglin, Melanie; Melar-New, Marta; Laimins, Laimonis (2009) Human papillomaviruses and the interferon response. J Interferon Cytokine Res 29:629-35
Moody, Cary A; Laimins, Laimonis A (2009) Human papillomaviruses activate the ATM DNA damage pathway for viral genome amplification upon differentiation. PLoS Pathog 5:e1000605
Cote-Martin, Alexandra; Moody, Cary; Fradet-Turcotte, Amelie et al. (2008) Human papillomavirus E1 helicase interacts with the WD repeat protein p80 to promote maintenance of the viral genome in keratinocytes. J Virol 82:1271-83
Regan, Jennifer A; Laimins, Laimonis A (2008) Bap31 is a novel target of the human papillomavirus E5 protein. J Virol 82:10042-51

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