The human papillomaviruses (HPVs) are causally linked to a number of human cancers. Over 100 different HPVs have been identified and many are associated with lesions that are at risk to progress to cancer. The papillomaviruses are divided into different genera based on the sequence relatedness of their genomes. Some of the alpha genus HPVs are associated with cervical cancer, other anogenital cancers, and approximately 20% of head and neck cancers. There is also suggestive but not yet compelling evidence implicating some of the beta genus HPVs in some non-melanoma skin cancers. The papillomavirus E2 gene product is conserved among papillomaviruses and functions as a major regulator of viral transcription, viral replication and genome maintenance. The E2 protein was first described in the 1980s to be a transcription factor that can activate viral transcription through E2 responsive elements located within the viral genome. E2 has additional functions however, and can serve either as a transactivator or a repressor of viral transcription depending upon the location and context of its binding sites within the viral genome. E2 is required for vira DNA replication as an auxiliary DNA replication factor that helps recruit the viral E1 helicase to the viral DNA replication origin. In addition, E2 is essential for genome maintenance in infected cells and, for some papillomaviruses, E2 functions by binding and linking the viral DNA to host cell mitotic chromosomes. In 2004 my laboratory identified the bromodomain protein Brd4 as a major E2 interacting protein and established its function as a cellular tether for the BPV E2/DNA complex on host mitotic chromosomes. In the past funding cycle, this grant focused on E2 and Brd4 and established additional roles for Brd4 in mediating various E2 functions. This grant renewal application focuses on E2.
The first aim recognizes that there is a broader need for understanding Brd4 itself and will further extend our knowledge of E2 and Brd4 functions. The second is a new area for this grant, proposing a broad non-biased analysis of HPV E2 protein interactions across 20 different HPV types. As an important multifunctional regulatory protein required for several different aspects of the viral life cycle, E2 is an attractive target for the development of HPV antivirals. An ultimate goal of these experiments is to gain further insights into the cellular proteins and pathways that both regulate and mediate E2 functions, with the expectation that one or more of them might have the potential to be exploited for the identification or development of small molecule inhibitors. Such compounds would be useful tools for further studies of HPV-host cell interactions and could serve as potential leads for modeling novel antivirals to treat papillomavirus infections.
The human papillomaviruses (HPVs) are a family of viruses that are associated with a number of human cancers. The E2 protein is a critical regulatory protein encoded by the papillomaviruses affecting viral transcription, viral DNA replication and viral genome maintenance. The cellular factors that regulate E2 as well as the cellular factors through which E2 affects its various functions are potential targets for the development of antiviral compounds for treating HPV associated lesions.
|Smith, Jennifer A; Haberstroh, Friederike S; White, Elizabeth A et al. (2014) SMCX and components of the TIP60 complex contribute to E2 regulation of the HPV E6/E7 promoter. Virology 468-470:311-21|
|French, Christopher A; Rahman, Shaila; Walsh, Erica M et al. (2014) NSD3-NUT fusion oncoprotein in NUT midline carcinoma: implications for a novel oncogenic mechanism. Cancer Discov 4:928-41|
|Rahman, Shaila; Sowa, Mathew E; Ottinger, Matthias et al. (2011) The Brd4 extraterminal domain confers transcription activation independent of pTEFb by recruiting multiple proteins, including NSD3. Mol Cell Biol 31:2641-52|
|Smith, Jennifer A; White, Elizabeth A; Sowa, Mathew E et al. (2010) Genome-wide siRNA screen identifies SMCX, EP400, and Brd4 as E2-dependent regulators of human papillomavirus oncogene expression. Proc Natl Acad Sci U S A 107:3752-7|
|Ottinger, Matthias; Smith, Jennifer A; Schweiger, Michal-Ruth et al. (2009) Cell-type specific transcriptional activities among different papillomavirus long control regions and their regulation by E2. Virology 395:161-71|
|Zheng, Gang; Schweiger, Michal-Ruth; Martinez-Noel, Gustavo et al. (2009) Brd4 regulation of papillomavirus protein E2 stability. J Virol 83:8683-92|
|Ottinger, Matthias; Pliquet, Daniel; Christalla, Thomas et al. (2009) The interaction of the gammaherpesvirus 68 orf73 protein with cellular BET proteins affects the activation of cell cycle promoters. J Virol 83:4423-34|
|You, Jianxin; Li, Qing; Wu, Chong et al. (2009) Regulation of aurora B expression by the bromodomain protein Brd4. Mol Cell Biol 29:5094-103|
|Schweiger, Michal-Ruth; Ottinger, Matthias; You, Jianxin et al. (2007) Brd4-independent transcriptional repression function of the papillomavirus e2 proteins. J Virol 81:9612-22|
|You, Jianxin; Srinivasan, Viswanathan; Denis, Gerald V et al. (2006) Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen interacts with bromodomain protein Brd4 on host mitotic chromosomes. J Virol 80:8909-19|
Showing the most recent 10 out of 12 publications