Human papillomaviruses (HPV) are the causative agents of cervical, anal and many oral cancers. While prophylactic vaccines to prevent HPV infections have been developed, there is no effective therapeutic treatment for existing HPV lesions. It is therefore of critical importance to understand how the productive life cycles of hig-risk HPVs are regulated to identify potential new therapeutic targets. HPVs infect stratified squamous epithelia and link their productive life cycles to the differentiation of the infected cel. My laboratory recently demonstrated that the amplification of HPV genomes in differentiating cells is dependent on activation of the ataxia-telangiectasia mutated (ATM) kinase pathway. Activation of this pathway is mediated by STAT-5 transcription factors that are regulated by the HPV E7 proteins. A second important pathway for genome amplification is the maintenance of cell proliferation ability in differentiating cells that is dependent upon p63 expression in suprabasal cells and is also controlled by E7. The overall goal of our studies is to understand how HPV modulates expression of cellular transcription factors as well as microRNAs to regulate pathways important for its differentiation-dependent productive life cycle. Our studies have identified the primary cellular transcription factors that directly activate the early and lat viral promoters. As part of this work we determined that p63 and STAT-5 play essential roles in controlling the late phase of the viral life cycle yet do not directly activate the HPV late promotr. These factors modulate cell proliferation as well as the ATM DNA damage pathways in differentiating epithelial cells, both of which are critical for inducing the late phase of the lif cycle. In HPV positive cells, a number of cellular microRNAs have been identified by our deep sequencing and likely are important regulators of the viral life cycle. These miRNAs target the same pathways controlling p63 as well as DNA damage activities. miR-203 regulates the HPV life cycle by modulating p63 levels while miR-145 controls differentiation-dependent expression of the cellular transcription factor, KLF-4, which is a downstream effector of p63 action. The goal of this application is to understand how these cellular transcription factors and microRNAs activate pathways that are critical for differentiation-dependent amplification of HPV genomes. We will ask the following questions: 1). How does STAT-5 activate the ATM DNA damage pathway in differentiating HPV positive keratinocytes? 2). How does p63 regulate DNA damage response and proliferation ability in differentiating HPV-positive keratinocytes? Is this linked to STAT-5 or Rb pocket protein pathways? 3). Do HPV-induced changes in expression of specific cellular microRNAs regulate HPV late functions?

Public Health Relevance

Cervical cancer is the second leading killer of women by cancer worldwide. Human papillomaviruses are the etiological agents of these cancers and they regulate their differentiation-dependent life cycles by activating DNA damage and p63 pathways. These studies will determine how HPV manipulates these pathways and so identify new ways to target this important process in women suffering from these malignancies.

National Institute of Health (NIH)
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Read-Connole, Elizabeth Lee
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Northwestern University at Chicago
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Gunasekharan, Vignesh Kumar; Li, Yan; Andrade, Jorge et al. (2016) Post-Transcriptional Regulation of KLF4 by High-Risk Human Papillomaviruses Is Necessary for the Differentiation-Dependent Viral Life Cycle. PLoS Pathog 12:e1005747
Langsfeld, Erika; Laimins, Laimonis A (2016) Human papillomaviruses: research priorities for the next decade. Trends Cancer 2:234-240
Langsfeld, Erika S; Bodily, Jason M; Laimins, Laimonis A (2015) The Deacetylase Sirtuin 1 Regulates Human Papillomavirus Replication by Modulating Histone Acetylation and Recruitment of DNA Damage Factors NBS1 and Rad51 to Viral Genomes. PLoS Pathog 11:e1005181
Galloway, Denise A; Laimins, Laimonis A (2015) Human papillomaviruses: shared and distinct pathways for pathogenesis. Curr Opin Virol 14:87-92
Hong, Shiyuan; Cheng, Shouqiang; Iovane, Andre et al. (2015) STAT-5 Regulates Transcription of the Topoisomerase IIβ-Binding Protein 1 (TopBP1) Gene To Activate the ATR Pathway and Promote Human Papillomavirus Replication. MBio 6:e02006-15
Hong, Shiyuan; Dutta, Anindya; Laimins, Laimonis A (2015) The acetyltransferase Tip60 is a critical regulator of the differentiation-dependent amplification of human papillomaviruses. J Virol 89:4668-75
Mehta, Kavi; Gunasekharan, Vignesh; Satsuka, Ayano et al. (2015) Human papillomaviruses activate and recruit SMC1 cohesin proteins for the differentiation-dependent life cycle through association with CTCF insulators. PLoS Pathog 11:e1004763
Pattabiraman, Chitra; Hong, Shiyuan; Gunasekharan, Vignesh K et al. (2014) CD66+ cells in cervical precancers are partially differentiated progenitors with neoplastic traits. Cancer Res 74:6682-92
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
Hong, Shiyuan; Laimins, Laimonis A (2013) Regulation of the life cycle of HPVs by differentiation and the DNA damage response. Future Microbiol 8:1547-57

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