The HPV16 E6 Oncoprotein Causes Prolonged Receptor Protein Tyrosine Kinase Signaling and Enhances Internalization of Phosphorylated Receptor Species

The high-risk human papillomavirus (HPV) E6 proteins are consistently expressed in HPV-associated lesions and cancers. HPV16 E6 sustains the activity of the mTORC1 and mTORC2 signaling cascades under conditions of growth factor deprivation. Here we report that HPV16 E6 activated mTORC1 by enhanced signaling through receptor protein tyrosine kinases, including epidermal growth factor receptor and insulin receptor and insulin-like growth factor receptors. This is evidenced by sustained signaling through these receptors for several hours after growth factor withdrawal. HPV16 E6 increased the internalization of activated receptor species, and the signaling adaptor protein GRB2 was shown to be critical for HPV16 E6 mediated enhanced EGFR internalization and mTORC1 activation. As a consequence of receptor protein kinase mediated mTORC1 activation, HPV16 E6 expression increased cellular migration of primary human epithelial cells. This study identifies a previously unappreciated mechanism by which HPV E6 proteins perturb host-signaling pathways presumably to sustain protein synthesis during the viral life cycle that may also contribute to cellular transforming activities of high-risk HPV E6 proteins

The Healing of America: The Path to Reconciliation

The 2016 presidential election exposed the presence of wide divisiveness in U.S. culture between political groups, racial groups, levels of education, rural and city areas, and religions. Expressions of polarization between groups occurred in episodes of violence, protests, marches, and disrespectful behavior among candidates. This article suggests that reconciliation between groups will not occur without a commitment to facing the truth about social problems in America, forgiveness for harms committed, demonstration of concern for the social welfare of the disadvantaged, and commitment to serving as agents of peace. Included is a case study that demonstrates how one community used many of these elements in their journey toward a more just community

Compassion: A Way to Live in Community

Beginning with a discussion about the meaning of compassion and its Judaic and Christian foundations, this article provides an understanding of how compassion builds and sustains community. It includes a model of the compassion process, a discussion of the barriers that prevent compassion from being expressed more freely, and examples about where compassion may need greater expression in our worl

Forgiveness: Healing Old Wounds

Because life in community will sometimes involve harmful words and actions, forgiveness may be one of the most important processes to heal and restore relationships. The ability to forgive involves healing in some combination of mind, heart and spirit and each of the dimensions may affect the others. This article explores the behaviors that must be present for genuine forgiveness to occur including the role of apology, and how these behaviors contribute to transforming broken spirits and restoring relationships

Late-and Post-Glacial History of the Greenwood Moraine and Adjacent River Valleys of South-Central Indiana

At the height of the last Ice Age, the northern part of North America was covered by the Laurentide Ice Sheet which contributed to the formation of the recessional feature found in south-central Indiana known as the Greenwood Moraine. Rivers draining from the moraine, flowing adjacent to it, and cutting through it evolved during the late- and post-glacial times. The purpose of this project is to understand the late- and post-glacial chronology of river development using absolute age data. Preliminary analyses suggest a straight-forward river evolution model consisting of several geomorphic processes, are presented herein

Regulation of Growth Factor and Nutrient Sensing Pathways by Human Papillomavirus E6 Proteins

High-risk human papillomaviruses (HPVs) are associated with nearly all cases of cervical cancer and also contribute to other types of anogenital and oropharyngeal cancers. The high-risk HPV E6 oncoprotein contributes to malignant progression in part by the targeted degradation of the tumor suppressor p53. The activation of growth factor and nutrient sensing pathways including receptor protein tyrosine kinases (RPTKs) and mTORC1 may also support cellular transformation. Moreover, previous studies suggested that HPV16 E6 activates mTORC1. We are particularly interested in understanding the mechanisms by which HPV E6 activates mTORC1 and the function of mTORC1 activation in HPV infection. Here we show that high-risk HPV16 E6 activates mTORC1 signaling and increases cap dependent translation through an increase in S6K signaling and an increase in 4E-BP1 phosphorylation. Mechanistically we found that HPV16 E6 activates AKT under conditions of nutrient deprivation. The combined approach of phospho-tyrosine immunoprecipitations and Western blot identified HPV16 E6 mediated activation of a subset of receptor protein tyrosine kinases. HPV16 E6 activates RPTKs at least in part by increasing the internalization of phosphorylated and activated receptor species. The signaling adaptor protein Grb2 associates with HPV16 E6, and Grb2 knockdown abrogated HPV16 E6 mediated mTORC1 activation. We hypothesize that Grb2 may be important in relaying E6 mediated RPTK activation to downstream signaling cascades. In this dissertation we also evaluate mTORC1 signaling and cap dependent translation in cells expressing HPV16 E6 mutants and E6 proteins from other HPV types. Binding to p53 and the association with proteins that contain an LXXLL motif are important for HPV16 E6 mediated mTORC1 activation. An increase in mTORC1 activation and cap dependent translation is shared between high-and low-risk mucosal, but not cutaneous HPV E6 proteins. Association with proteins through their LXXLL binding motif is also important for low-risk mucosal HPV E6 activation of mTORC1 and cap dependent translation. Shared mucosal E6 activation of mTORC1 indicates that mTORC1 may be important for the viral lifecycle in mucosal epithelia. However, it does not rule out the possibility that together with other properties of high-risk HPV E6 proteins, mTORC1 activation may promote transformation