Human papillomaviruses (HPV) cause very common infections of men, women and children. These are of particular medical importance and scientific significance since a subset of HPVs cause cancers of cervix, oropharynx, and anogenital region. In this grant proposal we investigate the functions of the E6 protein in HPV type 16, the most prevalent HPV associated with malignant progression.
Aim 1 is a comprehensive investigation of the molecular pathways and interacting partners of E6 that are essential for keratinocyte immortalization. Cancer associated HPV E6 proteins bind and degrade the tumor suppressor p53 and stimulate expression of the catalytic component of telomerase hTERT. HPV-16 E6 also binds to other cellular proteins, but the significance of these interactions is largely unknown. We reported that the E6 interacting protein Ada3, which binds p53 and histone acetyltransferases, mediates p53 acetylation and induction of cell senescence. Recent results demonstrate an additional role for E6 and p53 acetylation in autophagic cell death. E6 is also necessary for stable viral genome replication and in Aim 2, we explore the functions of E6 that are necessary for viral replication in monolayer culture in which the genome is maintained as low copy episomes and in differentiated keratinocyte models that reproduce the stage of viral genome amplification. In this grant proposal, we combine the use of well-characterized HPV-16 E6 mutations, RNA silencing, and expression of dominant negative cellular factors to decipher their functions in human keratinocyte immortalization and HPV genome replication. This research project has already produced novel insights into the molecular pathways that govern p53 activity, escape from replicative senescence, and neoplastic progression and will result in new understandings of the contributions of E6 to replication of episomal HPV genomes and potential targets for HPV E6 directed therapeutics.
Lay Statement: Papillomaviruses cause benign infections that can become malignant. The viral protein called E6 is necessary for viral replication and can induce early steps of cancer in cells grown outside the body. The purpose of this grant is to determine the specific activities of this protein that are necessary for the virus to grow and cause cancer. The results will lead to new insights into the mechanisms that control cell growth. Furthermore, as we understand how the virus manipulates the host cell, this may enable development of drugs that specifically target viral proteins that can be used to treat papillomavirus induced cervical, anogenital and head and neck cancers and their precursor lesions.
|Rietz, Anne; Petrov, Dino P; Bartolowits, Matthew et al. (2016) Molecular Probing of the HPV-16 E6 Protein Alpha Helix Binding Groove with Small Molecule Inhibitors. PLoS One 11:e0149845|
|Lakhter, Alexander J; Sahu, Ravi P; Sun, Yang et al. (2013) Chloroquine promotes apoptosis in melanoma cells by inhibiting BH3 domain-mediated PUMA degradation. J Invest Dermatol 133:2247-54|
|Cherry, Jonathan J; Rietz, Anne; Malinkevich, Anna et al. (2013) Structure based identification and characterization of flavonoids that disrupt human papillomavirus-16 E6 function. PLoS One 8:e84506|
|Androphy, Elliot J (2013) Genomic instability: Ada3 and HPV E6-acetyltransferase connections? Cell Cycle 12:13|
|D'Costa, Zarina J; Jolly, Carol; Androphy, Elliot J et al. (2012) Transcriptional repression of E-cadherin by human papillomavirus type 16 E6. PLoS One 7:e48954|
|Naidu, Samisubbu R; Lakhter, Alexander J; Androphy, Elliot J (2012) PIASy-mediated Tip60 sumoylation regulates p53-induced autophagy. Cell Cycle 11:2717-28|
|Love, Ian M; Sekaric, Pedja; Shi, Dingding et al. (2012) The histone acetyltransferase PCAF regulates p21 transcription through stress-induced acetylation of histone H3. Cell Cycle 11:2458-66|
|Naidu, S R; Love, I M; Imbalzano, A N et al. (2009) The SWI/SNF chromatin remodeling subunit BRG1 is a critical regulator of p53 necessary for proliferation of malignant cells. Oncogene 28:2492-501|
|Shamanin, Vladimir A; Sekaric, Pedja; Androphy, Elliot J (2008) hAda3 degradation by papillomavirus type 16 E6 correlates with abrogation of the p14ARF-p53 pathway and efficient immortalization of human mammary epithelial cells. J Virol 82:3912-20|
|Sekaric, Pedja; Cherry, Jonathan J; Androphy, Elliot J (2008) Binding of human papillomavirus type 16 E6 to E6AP is not required for activation of hTERT. J Virol 82:71-6|
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