Friday, May 9, 2025
5/9/2025
Human papillomavirus regulation of the Hippo signaling pathway - PROJECT SUMMARY/ABSTRACT High-risk human papillomavirus (HPV) infection is responsible for nearly 5% of the global cancer burden. HPVs establish persistent infections in the basal layer of stratified squamous epithelia, and virus persistence is an essential precursor to carcinogenesis. However, epithelial tissues are dynamic. There is a major open question regarding how HPV-infected cells are retained in the basal layer for years to decades in the face of constant epithelial cell turnover. Our research on the HPV E7 protein has revealed a role for E7 in maintaining HPV- infected cells in the basal epithelial layer, an activity that we anticipate is required for HPV carcinogenesis. We propose that HPV E7 disrupts the balance between proliferation and differentiation that normally occurs in stratified epithelia, favoring the retention of some infected cells in the basal epithelial layer to harbor persistent infection, but not completely blocking other cells from differentiating to support productive infection. Our published data show that HPV E7 proteins degrade the tumor suppressor PTPN14, activating the YAP1 oncoprotein. Unexpectedly, HPV E7 activates YAP1 only in cells in the basal layer of stratified epithelia, where YAP1 drives cell stemness and self-renewal. We found that HPV E7 must degrade PTPN14 and activate YAP1 to immortalize human epithelial cells and to promote their basal epithelial identity. The goal of this proposal is to test the model that PTPN14 is essential in the pathway that triggers basal cell commitment to differentiation. We propose that transcriptional activating (TA) isoforms of the transcription factor p63 drive PTPN14 expression specifically in basal epithelial cells. TAp63 promotes commitment to epithelial differentiation and a p63- dependent super-enhancer controls PTPN14. Our data support that PTPN14 can promote Hippo kinase cascade signaling, thereby inhibiting YAP1 and driving commitment to epithelial differentiation. Our hypothesis is that HPV E7 oncoproteins reduce Hippo pathway signaling and activate YAP1 by degrading PTPN14, a protein that enables the p63-dependent commitment to differentiation in basal epithelial cells. The aims are 1) to elucidate the mechanism by which HPV E7-mediated PTPN14 degradation activates YAP1 and 2) to determine how PTPN14 is regulated by p63 in HPV-positive and HPV-negative stratified epithelia. Our research will advance the understanding of how HPV E7 drives carcinogenesis and how HPV infections persist in basal epithelial cells. Using HPV as a tool, we will elucidate a fundamental mechanism in epithelial biology, with the potential to identify new therapeutic interventions for HPV-related diseases based on mechanistic insights.
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