Modulation of p53-Dependent Differentiation Signaling Through Molecular Interactions Between the HPV E6 Oncoprotein and the Actin-Binding Transcriptional Cofactor, MKL1
The high-risk human papillomaviruses infect basal epithelial stem cells within oropharyngeal or anogenital mucosal membranes and have been etiologically linked to uterine cervical dysplasia as well as to several HPV+ epithelial malignancies, including cervical squamous-cell carcinomas, vaginal, penile, and anogenital cancers, and certain subsets of head-and-neck/oropharyngeal cancers. Despite the widespread availability of multivalent preventive vaccines against the major hrHPV subtypes, more than 45,000 new cases of cervical cancer are diagnosed each year in the United States and the incidences of oropharyngeal and anogenital cancers have continued to increase, particularly, among HPV-infected subpopulations. The vegetative replication of the viral dsDNA genome (episome) and the production of infectious virus particles within infected epithelial cells are intricately linked to the keratinocyte differentiation program and are mediated by the HPV early proteins: E1, E2, E4, E5, E6, and E7. Intriguingly, the ability of the virus to reproduce within differentiated spinous epithelial cells and granular keratinocytes is dependent upon the reprogramming of these cells to express various S-phase promoting components by the viral E6 and E7 oncoproteins. The molecular mechanisms by which hrHPVs inhibit cellular differentiation signaling are not completely understood. We therefore hypothesize that MKL1 and cytoskeletal dynamics could influence the expression of p53-regulated differentiation genes targeted by the E6 oncoprotein.
Dr. Robert Harrod
Dr. Edward Glasscock
Dr. Zhihao Wu
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Kurtaneck, Nicholas, "Modulation of p53-Dependent Differentiation Signaling Through Molecular Interactions Between the HPV E6 Oncoprotein and the Actin-Binding Transcriptional Cofactor, MKL1" (2022). Biological Sciences Theses and Dissertations. 17.
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