scholarly journals YAP1 Activation by Human Papillomavirus E7 Promotes Basal Cell Identity in Squamous Epithelia

2021 ◽  
Author(s):  
Joshua Hatterschide ◽  
Paola Castagnino ◽  
Hee Won Kim ◽  
Steven M Sperry ◽  
Kathleen T Montone ◽  
...  
Keyword(s):  
Human Papillomavirus ◽  
Epithelial Cells ◽  
Hippo Pathway ◽  
Hpv Infection ◽  
Anatomical Site ◽  
Hippo Signaling ◽  
Basal Cells ◽  
Carcinogenic Activity ◽  
E7 Oncoprotein ◽  
Hpv E7

Persistent human papillomavirus (HPV) infection of stratified squamous epithelial cells causes nearly five percent of cancer cases worldwide. HPV-positive oropharyngeal cancers harbor few mutations in the Hippo signaling pathway compared to HPV-negative cancers at the same anatomical site, prompting the hypothesis that an HPV-encoded protein inactivates the Hippo pathway and activates the Hippo effector YAP1. The HPV E7 oncoprotein is required for HPV infection and for HPV-mediated oncogenic transformation. We investigated the effects of HPV oncoproteins on YAP1 and found that E7 activates YAP1, promoting YAP1 nuclear localization in basal epithelial cells. YAP1 activation by HPV E7 required that E7 bind and degrade the tumor suppressor PTPN14. E7 required YAP1 transcriptional activity to extend the lifespan of primary keratinocytes, indicating that YAP1 activation contributes to E7 carcinogenic activity. Maintaining infection in basal cells is critical for HPV persistence, and here we demonstrate that YAP1 activation causes HPV E7 expressing cells to be retained in the basal compartment of stratified epithelia. We propose that YAP1 activation resulting from PTPN14 inactivation is an essential, targetable activity of the HPV E7 oncoprotein relevant to HPV infection and carcinogenesis.

scholarly journals EGF Receptor–Dependent YAP Activation Is Important for Renal Recovery from AKI

2018 ◽  
Vol 29 (9) ◽  
pp. 2372-2385 ◽  
Author(s):  
Jianchun Chen ◽  
Huaizhou You ◽  
Yan Li ◽  
You Xu ◽  
Qian He ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Cell Cycle Progression ◽  
Egf Receptor ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Hippo Pathway ◽  
Critical Role ◽  
Renal Recovery ◽  
Binding Motif ◽  
Hippo Signaling

BackgroundIncreasing evidence indicates that renal recovery from AKI stems from dedifferentiation and proliferation of surviving tubule epithelial cells. Both EGF receptor (EGFR) and the Hippo signaling pathway are implicated in cell proliferation and differentiation, and previous studies showed that activation of EGFR in renal proximal tubule epithelial cells (RPTCs) plays a critical role in recovery from ischemia-reperfusion injury (IRI). In this study, we explored RPTC activation of Yes-associated protein (YAP) and transcriptional coactivator with PDZ binding motif (TAZ), two key downstream effectors of the Hippo pathway, and their potential involvement in recovery from AKI.MethodsWe used immunofluorescence to examine YAP expression in kidney biopsy samples from patients with clinical AKI and controls (patients with minimal change disease). Studies of RPTC activation of YAP and TAZ used cultured human RPTCs that were exposed to hypoxia-reoxygenation as well as knockout mice (with inducible deletions of Yap, Taz, or both occurring specifically in RPTCs) that were subjected to bilateral IRI.ResultsYAP was activated in RPTCs in kidneys from post-AKI patients and post-IRI mouse kidneys. Inhibition of the interaction of YAP and the TEA domain (TEAD) transcription factor complex by verteporfin or conditional deletion of YAP in RPTCs delayed renal functional and structural recovery from IRI, whereas TAZ deletion had no effect. Activation of the EGFR-PI3K-Akt pathway in response to IRI signaled YAP activation, which promoted cell cycle progression.ConclusionsThis study shows that EGFR-PI3K-Akt–dependent YAP activation plays an essential role in mediating epithelial cell regeneration during kidney recovery from AKI.

scholarly journals Epidemiology and Burden of Human Papillomavirus and Related Diseases, Molecular Pathogenesis, and Vaccine Evaluation

2021 ◽  
Vol 8 ◽  
Author(s):  
Arnaud John Kombe Kombe ◽  
Bofeng Li ◽  
Ayesha Zahid ◽  
Hylemariam Mihiretie Mengist ◽  
Guy-Armel Bounda ◽  
...  
Keyword(s):  
Human Papillomavirus ◽  
System Development ◽  
Hpv Vaccination ◽  
Hpv Infection ◽  
Cold Chain ◽  
Anatomical Site ◽  
Upper Aerodigestive Tract ◽  
Vaccination Programs ◽  
High Risk Women ◽  
Novel Approach

Diagnosed in more than 90% of cervical cancers, the fourth deadliest cancer in women, human papillomavirus (HPV) is currently the most common pathogen responsible for female cancers. Moreover, HPV infection is associated with many other diseases, including cutaneous and anogenital warts, and genital and upper aerodigestive tract cancers. The incidence and prevalence of these pathologies vary considerably depending on factors including HPV genotype, regional conditions, the study population, and the anatomical site sampled. Recently, features of the cervicovaginal microbiota are found to be associated with the incidence of HPV-related diseases, presenting a novel approach to identify high-risk women through both blood and cervical samples. Overall, the HPV repartition data show that HPV infection and related diseases are more prevalent in developing countries. Moreover, the available (2-, 4-, and 9-valent) vaccines based on virus-like particles, despite their proven effectiveness and safety, present some limitations in terms of system development cost, transport cold chain, and oncogenic HPV variants. In addition, vaccination programs face some challenges, leading to a considerable burden of HPV infection and related diseases. Therefore, even though the new (9-valent) vaccine seems promising, next-generation vaccines as well as awareness programs associated with HPV vaccination and budget reinforcements for immunization are needed.

scholarly journals Poly(rC)-Binding Protein 2 Regulates Hippo Signaling To Control Growth in Breast Epithelial Cells

2016 ◽  
Vol 36 (16) ◽  
pp. 2121-2131 ◽  
Author(s):  
Fengmin Li ◽  
Kimberly Z. Bullough ◽  
Ajay A. Vashisht ◽  
James A. Wohlschlegel ◽  
Caroline C. Philpott
Keyword(s):  
Epithelial Cells ◽  
Target Genes ◽  
Hippo Pathway ◽  
Control Cell ◽  
Tissue Growth ◽  
Hippo Signaling ◽  
Breast Epithelial Cells ◽  
Mouse Tissues ◽  
Kinase Cascade ◽  
Breast Epithelial

Poly(rC)-binding proteins (PCBPs) are multifunctional adapters that mediate interactions between nucleic acids, iron cofactors, and other proteins, affecting the fates and activities of the components of these interactions. Here, we show that PCBP2 forms a complex with the Hippo pathway components Salvador (Sav1), Mst1, Mst2, and Lats1 in human cells and mouse tissues. Hippo is a kinase cascade that functions to phosphorylate and inactivate the transcriptional coactivators YAP and TAZ, which control cell growth and proliferation. PCBP2 specifically interacts with the scaffold protein Sav1 and prevents proteolytic cleavage of the Mst1 kinase, resulting in increased signaling through Hippo and suppressed activity of YAP and TAZ. Human breast epithelial cells lacking PCBP2 exhibit impaired proteasomal degradation of TAZ. They accumulate TAZ in both the nucleus and the cytosol, increase expression of YAP and TAZ connective tissue growth factor (CTGF) and Cyr61 target genes, and exhibit anchorage-independent growth. Thus, PCBP2 can function as a component of the Hippo complex, enhancing signaling, suppressing activity of YAP and TAZ, and altering the growth characteristics of cells.

Incidence and clearance of penile human papillomavirus infection among circumcised Kenyan men

2020 ◽  
Vol 31 (12) ◽  
pp. 1202-1211
Author(s):  
Danielle M Backes ◽  
Claire Bosire ◽  
Michael G Hudgens ◽  
Ali Fokar ◽  
Kawango Agot ◽  
...  
Keyword(s):  
Human Papillomavirus ◽  
High Risk ◽  
Infection Type ◽  
Cumulative Risk ◽  
Hpv Infection ◽  
Incidence Rates ◽  
Low Risk ◽  
Anatomical Site ◽  
Resource Limited ◽  
Geographical Regions

Prospective data are limited on human papillomavirus (HPV) acquisition and clearance among circumcised men from resource-limited geographical regions, particularly Africa. The goal of this study was to estimate incidence and clearance of type-specific genital HPV infection in men. Penile exfoliated cell specimens were collected from the glans/coronal sulcus and shaft of 1,037 circumcised Kenyan men at baseline and 6-, 12- and 18-month follow-up visits between 2003–2007. Specimens were tested with GP5+/6+ PCR to detect 44 HPV types. The median age of participants at baseline was 21 years (range 18–28). The 12- and 18-month incidence rates (IRs) for any HPV were 34.9/100 person-years (95% confidence interval [CI]: 31.2–39.0) and 36.4/100 person-years (95% CI: 32.9–40.2), respectively. The 18-month cumulative risk for high-risk HPV was 30% compared to 16% for low-risk HPV. Cumulative risk was not associated with age or anatomical site. The estimated probability of any HPV infection clearing by 12 months was 0.92. Time until HPV clearance was not associated with age, anatomical site, or whether HPV infection type was high-risk or low-risk. HPV IRs among circumcised men in this study were comparable to other circumcised populations.

scholarly journals APOBEC3A Functions as a Restriction Factor of Human Papillomavirus

2014 ◽  
Vol 89 (1) ◽  
pp. 688-702 ◽  
Author(s):  
Cody J. Warren ◽  
Tao Xu ◽  
Kejun Guo ◽  
Laura M. Griffin ◽  
Joseph A. Westrich ◽  
...  
Keyword(s):  
Head And Neck ◽  
Cancer Progression ◽  
Host Defense ◽  
Defense Mechanisms ◽  
Hpv Infection ◽  
Human Papillomaviruses ◽  
Head And Neck Cancers ◽  
Restriction Factor ◽  
E7 Oncoprotein ◽  
Hpv E7

ABSTRACTHuman papillomaviruses (HPVs) are small DNA viruses causally associated with benign warts and multiple cancers, including cervical and head-and-neck cancers. While the vast majority of people are exposed to HPV, most instances of infection are cleared naturally. However, the intrinsic host defense mechanisms that block the early establishment of HPV infections remain mysterious. Several antiviral cytidine deaminases of the human APOBEC3 (hA3) family have been identified as potent viral DNA mutators. While editing of HPV genomes in benign and premalignant cervical lesions has been demonstrated, it remains unclear whether hA3 proteins can directly inhibit HPV infection. Interestingly, recent studies revealed that HPV-positive cervical and head-and-neck cancers exhibited higher rates of hA3 mutation signatures than most HPV-negative cancers. Here, we report that hA3A and hA3B expression levels are highly upregulated in HPV-positive keratinocytes and cervical tissues in early stages of cancer progression, potentially through a mechanism involving the HPV E7 oncoprotein. HPV16 virions assembled in the presence of hA3A, but not in the presence of hA3B or hA3C, have significantly decreased infectivity compared to HPV virions assembled without hA3A or with a catalytically inactive mutant, hA3A/E72Q. Importantly, hA3A knockdown in human keratinocytes results in a significant increase in HPV infectivity. Collectively, our findings suggest that hA3A acts as a restriction factor against HPV infection, but the induction of this restriction mechanism by HPV may come at a cost to the host by promoting cancer mutagenesis.IMPORTANCEHuman papillomaviruses (HPVs) are highly prevalent and potent human pathogens that cause >5% of all human cancers, including cervical and head-and-neck cancers. While the majority of people become infected with HPV, only 10 to 20% of infections are established as persistent infections. This suggests the existence of intrinsic host defense mechanisms that inhibit viral persistence. Using a robust method to produce infectious HPV virions, we demonstrate that hA3A, but not hA3B or hA3C, can significantly inhibit HPV infectivity. Moreover, hA3A and hA3B were coordinately induced in HPV-positive clinical specimens during cancer progression, likely through an HPV E7 oncoprotein-dependent mechanism. Interestingly, HPV-positive cervical and head-and-neck cancer specimens were recently shown to harbor significant amounts of hA3 mutation signatures. Our findings raise the intriguing possibility that the induction of this host restriction mechanism by HPV may also trigger hA3A- and hA3B-induced cancer mutagenesis.

scholarly journals Inactivation of both the Retinoblastoma Tumor Suppressor and p21 by the Human Papillomavirus Type 16 E7 Oncoprotein Is Necessary To Inhibit Cell Cycle Arrest in Human Epithelial Cells

2002 ◽  
Vol 76 (20) ◽  
pp. 10559-10568 ◽  
Author(s):  
Anna-Marija Helt ◽  
Jens Oliver Funk ◽  
Denise A. Galloway
Keyword(s):  
Cell Cycle ◽  
Human Papillomavirus ◽  
Tumor Suppressor ◽  
Epithelial Cells ◽  
Cell Cycle Arrest ◽  
Cell Cycle Control ◽  
E7 Oncoprotein ◽  
Retinoblastoma Tumor Suppressor ◽  
Cycle Arrest ◽  
Retinoblastoma Tumor

ABSTRACT The human papillomavirus (HPV) type 16 E7 oncoprotein must inactivate the retinoblastoma tumor suppressor (Rb) pathway to bypass G1 arrest. However, E7 C-terminal mutants that were able to inactivate Rb were unable to bypass DNA damage-induced G1 arrest and keratinocyte senescence, suggesting that the E7 C terminus may target additional G1 regulators. The E7 C-terminal mutant proteins E7 CVQ68-70AAA and E7 Δ79-83 (deletion of positions 79 through 83) were further tested in several models of cell cycle arrest associated with elevated levels of p21. C-terminal mutations rendered E7 unable to induce S phase and endoreduplication in differentiated keratinocytes and rendered it less efficient in delaying senescence of human mammary epithelial cells. Interestingly, when cell cycle arrest was induced with a peptide form of p21, the E7 C-terminal mutants were deficient in overcoming arrest, whereas a mutant defective in Rb binding was competent in inhibiting G1 arrest. These results suggest that the inactivation of both p21 and Rb by E7 contributes to subversion of cell cycle control in normal human epithelia but that neither p21 nor Rb inactivation alone is sufficient.

scholarly journals Structural Analysis Reveals an Amyloid Form of the Human Papillomavirus Type 16 E1∧E4 Protein and Provides a Molecular Basis for Its Accumulation

2008 ◽  
Vol 82 (16) ◽  
pp. 8196-8203 ◽  
Author(s):  
Pauline B. McIntosh ◽  
Stephen R. Martin ◽  
Deborah J. Jackson ◽  
Jameela Khan ◽  
Erin R. Isaacson ◽  
...  
Keyword(s):  
Human Papillomavirus ◽  
Structural Analysis ◽  
Epithelial Cells ◽  
Molecular Basis ◽  
Hpv Infection ◽  
Fibril Formation ◽  
Amyloid Imaging ◽  
Biopsy Material ◽  
Human Papillomavirus Type 16 ◽  
Imaging Probes

ABSTRACT The abundant human papillomavirus (HPV) type 16 E4 protein exists as two distinct structural forms in differentiating epithelial cells. Monomeric full-length 16E1∧E4 contains a limited tertiary fold constrained by the N and C termini. N-terminal deletions facilitate the assembly of E1∧E4 into amyloid-like fibrils, which bind to thioflavin T. The C-terminal region is highly amyloidogenic, and its deletion abolishes amyloid staining and prevents E1∧E4 accumulation. Amyloid-imaging probes can detect 16E1∧E4 in biopsy material, as well as 18E1∧E4 and 33E1∧E4 in monolayer cells, indicating structural conservation. Our results suggest a role for fibril formation in facilitating the accumulation of E1∧E4 during HPV infection.

scholarly journals High-Risk Human Papillomavirus E7 Alters Host DNA Methylome and Represses HLA-E Expression in Human Keratinocytes

2017 ◽  
Author(s):  
Louis Cicchini ◽  
Rachel Z. Blumhagen ◽  
Joseph A. Westrich ◽  
Mallory E. Meyers ◽  
Cody J. Warren ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Human Papillomavirus ◽  
High Risk ◽  
Protein Expression ◽  
Cpg Island ◽  
Hpv Infection ◽  
Dependent Manner ◽  
Hpv E7 ◽  
E Protein

ABSTRACTHuman papillomavirus (HPV) infection distinctly alters methylation patterns in HPV-associated cancer. We have recently reported that HPV E7-dependent promoter hypermethylation leads to downregulation of the chemokine CXCL14 and suppression of antitumor immune responses. To investigate the extent of gene expression dysregulated by HPV E7-induced DNA methylation, we analyzed parallel global gene expression and DNA methylation using normal immortalized keratinocyte lines, NIKS, NIKS-16, NIKS-18, and NIKS-16ΔE7. We show that expression of the MHC class I genes is downregulated in HPV-positive keratinocytes in an E7-dependent manner. Methylome analysis revealed hypermethylation at a distal CpG island (CGI) near the HLA-E gene in NIKS-16 cells compared to either NIKS cells or NIKS-16ΔE7 cells, which lack E7 expression. The HLA-E CGI functions as an active promoter element which is dramatically repressed by DNA methylation. HLA-E protein expression on cell surface is downregulated by high-risk HPV16 and HPV18 E7 expression, but not by low-risk HPV6 and HPV11 E7 expression. Conversely, demethylation at the HLA-E CGI restores HLA-E protein expression in HPV-positive keratinocytes. Because HLA-E plays an important role in antiviral immunity by regulating natural killer and CD8+ T cells, epigenetic downregulation of HLA-E by high-risk HPV E7 may contribute to virus-induced immune evasion during HPV persistence.

scholarly journals A conserved amino acid in the C-terminus of HPV E7 mediates binding to PTPN14 and repression of epithelial differentiation

2020 ◽  
Author(s):  
Joshua Hatterschide ◽  
Alexis C. Brantly ◽  
Miranda Grace ◽  
Karl Munger ◽  
Elizabeth A. White
Keyword(s):  
Gene Expression ◽  
Human Papillomavirus ◽  
Life Cycle ◽  
Human Keratinocytes ◽  
Keratinocyte Differentiation ◽  
Carcinogenic Activity ◽  
Hpv E7 ◽  
Primary Driver ◽  
E7 Proteins ◽  
High Risk Hpv

ABSTRACTThe human papillomavirus (HPV) E7 oncoprotein is a primary driver of HPV-mediated carcinogenesis. The E7 proteins from diverse HPV bind to the host cellular non-receptor protein tyrosine phosphatase type 14 (PTPN14) and direct it for degradation through the activity of the E7-associated host E3 ubiquitin ligase UBR4. Herein we show that a highly conserved arginine residue in the C-terminal domain of diverse HPV E7 mediates interaction with PTPN14. We found that disruption of PTPN14 binding through mutation of the C-terminal arginine did not impact the ability of several high-risk HPV E7 proteins to bind and degrade the retinoblastoma tumor suppressor or activate E2F target gene expression. HPVs infect human keratinocytes and we previously reported that both PTPN14 degradation by HPV16 E7 and PTPN14 CRISPR knockout repress keratinocyte differentiation-related genes. Now we have found that blocking PTPN14 binding through mutation of the conserved C-terminal arginine rendered both HPV16 and HPV18 E7 unable to repress differentiation-related gene expression. We then confirmed that the HPV18 E7 variant that could not bind PTPN14 was also impaired in repressing differentiation when expressed from the complete HPV18 genome. Finally, we found that the ability of HPV18 E7 to extend the lifespan of primary human keratinocytes required PTPN14 binding. CRISPR/Cas9 knockout of PTPN14 rescued keratinocyte lifespan extension in the presence of the PTPN14 binding-deficient HPV18 E7 variant. These results support the model that PTPN14 degradation by high-risk HPV E7 leads to repression of differentiation and contributes to its carcinogenic activity.IMPORTANCEHuman papillomavirus (HPV)-positive carcinomas account for nearly 5% of the global human cancer burden. The E7 oncoprotein is a primary driver of HPV-mediated carcinogenesis. HPV E7 binds and degrades the putative tumor suppressor, PTPN14. However, the impact of PTPN14 binding by E7 on cellular processes is not well defined. Here, we show that PTPN14 binding is mediated by a conserved C-terminal arginine residue of HPV E7 in vivo. Additionally, we found that PTPN14 binding contributes to the carcinogenic activity of HPV18 E7 (the second most abundant HPV type in cancers). Finally, we determined that PTPN14 binding by HPV16 E7 and HPV18 E7 represses keratinocyte differentiation. HPV-positive cancers are frequently poorly differentiated and the HPV life cycle is dependent upon the keratinocyte differentiation program. The finding that PTPN14 binding by HPV E7 impairs differentiation has significant implications for both HPV-mediated carcinogenesis and the HPV life cycle.

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