Infection with the high risk types of human papillomaviruses (HPVs) is strongly linked to the development of cancers of the uterine cervix. Carcinogenesis depends upon the continuous expression of the viral E6 and E7 oncogenes in the affected individual. Transcription of these oncogenes is negatively regulated by the viral E2 protein, and indeed, disruption of the E2 open reading frame usually marks the carcinogenic progression of cervical lesions. When reintroduced into HPV positive cancer cells, E2 proteins suppress cellular growth through senescence induction. E2 repression of E6/E7 is necessary and sufficient for this process, indicating that important senescence mediators must be controlled by the viral oncoproteins. Previous studies of the transcriptome of E2 expressing, senescent HeLa cells revealed consistent repression of the human DEK proto-oncogene. DEK expression has been associated with human carcinogenesis, however, little is known about intracellular DEK functions and its pathophysiological role is thus not known. Our data demonstrate DEK repression during both E2 induced and replicative senescence, and discover functional roles for this molecule as a senescence inhibitor. In agreement with potential pro-carcinogenic activities, we identify DEK as an upregulated target of the high risk HPV E7 as well as the adenovirus E1A oncogene. RNA interference studies reveal that DEK expression is necessary for cancer cell survival and additionally uncover anti-apoptotic activities. This grant application aims to investigate the molecular mechanism by which normal and viral oncogene induced DEK expression is regulated, to distinguish specific senescence inhibitory from anti-apoptotic DEK functions and to shed light on the signaling pathways that govern the respective processes. To assess the potential relevance of our findings for the diagnosis and treatment of cancer, we will examine whether DEK expression is elevated in HPV positive tumors. HPV is the most frequently sexually transmitted pathogen in the U.S. and the cause of cervical cancer, the second most prevalent cancer worldwide. We study the aberrant upregulation and activity of a cellular gene DEK in cervical cancer cells. We will determine how DEK is upregulated by the HPV E7 oncoprotein and how it may help stimulate cervical cancer growth, with potential implications for its use as a diagnostic marker and drug target in cervical and other cancer patients. ? ? ?
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| Serrano-Lopez, Juana; Nattamai, Kalpana; Pease, Nicholas A et al. (2018) Loss of DEK induces radioresistance of murine restricted hematopoietic progenitors. Exp Hematol 59:40-50.e3 |
| Smith, Eric A; Kumar, Bhavna; Komurov, Kakajan et al. (2017) DEK associates with tumor stage and outcome in HPV16 positive oropharyngeal squamous cell carcinoma. Oncotarget 8:23414-23426 |
| Matrka, Marie C; Watanabe, Miki; Muraleedharan, Ranjithmenon et al. (2017) Overexpression of the human DEK oncogene reprograms cellular metabolism and promotes glycolysis. PLoS One 12:e0177952 |
| Smith, Eric A; Gole, Boris; Willis, Nicholas A et al. (2017) DEK is required for homologous recombination repair of DNA breaks. Sci Rep 7:44662 |
| Privette Vinnedge, L M; Benight, N M; Wagh, P K et al. (2015) The DEK oncogene promotes cellular proliferation through paracrine Wnt signaling in Ron receptor-positive breast cancers. Oncogene 34:2325-36 |
| Matrka, Marie C; Hennigan, Robert F; Kappes, Ferdinand et al. (2015) DEK over-expression promotes mitotic defects and micronucleus formation. Cell Cycle 14:3939-53 |
| Adams, Allie K; Bolanos, Lyndsey C; Dexheimer, Phillip J et al. (2015) IRAK1 is a novel DEK transcriptional target and is essential for head and neck cancer cell survival. Oncotarget 6:43395-407 |
| Adams, A K; Hallenbeck, G E; Casper, K A et al. (2015) DEK promotes HPV-positive and -negative head and neck cancer cell proliferation. Oncogene 34:868-77 |
| Adams, Allie K; Wise-Draper, Trisha M; Wells, Susanne I (2014) Human papillomavirus induced transformation in cervical and head and neck cancers. Cancers (Basel) 6:1793-820 |
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