scholarly journals The High-Risk Human Papillomavirus Type 16 E6 Counters the GAP Function of E6TP1 toward Small Rap G Proteins

2003 ◽  
Vol 77 (2) ◽  
pp. 1614-1620 ◽  
Author(s):  
Latika Singh ◽  
Qingshen Gao ◽  
Ajay Kumar ◽  
Takaya Gotoh ◽  
David E. Wazer ◽  
...  
Keyword(s):  
Human Papillomavirus ◽  
High Risk ◽  
G Protein ◽  
Mutational Analysis ◽  
Protein Signaling ◽  
Hpv16 E6 ◽  
Human Papillomavirus Type 16 ◽  
Hpv E6 ◽  
Small G Protein ◽  
Transforming Activity

ABSTRACT We have recently identified E6TP1 (E6-targeted protein 1) as a novel high-risk human papillomavirus type 16 (HPV16) E6-binding protein. Importantly, mutational analysis of E6 revealed a strong correlation between the transforming activity and its abilities to bind and target E6TP1 for ubiquitin-mediated degradation. As a region within E6TP1 has high homology with GAP domains of known and putative Rap GTPase-activating proteins (GAPs), these results raised the possibility that HPV E6 may alter the Rap small-G-protein signaling pathway. Using two different approaches, we now demonstrate that human E6TP1 exhibits GAP activity for Rap1 and Rap2, confirming recent findings that a closely related rat homologue exhibits Rap-specific GAP activity. Using mutational analysis, we localize the GAP activity to residues 240 to 945 of E6TP1. Significantly, we demonstrate that coexpression of HPV16 E6, by promoting the degradation of E6TP1, enhances the GTP loading of Rap. These results support a role of Rap small-G-protein pathway in E6-mediated oncogenesis.

scholarly journals Identification of High-Risk Human Papillomavirus DNA, p16 and E6/E7 Oncoproteins in Laryngeal and Hypopharyngeal Squamous Cell Carcinomas

Viruses ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1008
Author(s):  
Andrejs Lifsics ◽  
Valerija Groma ◽  
Maksims Cistjakovs ◽  
Sandra Skuja ◽  
Renars Deksnis ◽  
...  
Keyword(s):  
Human Papillomavirus ◽  
High Risk ◽  
Squamous Cell ◽  
Surrogate Marker ◽  
Hpv Infection ◽  
Hpv16 E6 ◽  
Hpv Dna ◽  
Molecular Virology ◽  
Hpv E6 ◽  
E6 And E7

Human papillomavirus (HPV) was proven to play a significant role in cancer development in the oropharynx. However, its role in the development of laryngeal (LSCC) and hypopharyngeal squamous cell carcinoma (HPSCC) remains to be clarified. High-risk HPV (HR-HPV) viral proteins E6 and E7 are considered to be pertinent to HPV-related carcinogenesis. Hence, our aim was to estimate LSCC and HPSCC for HR-HPV DNA, p16, and E6/E7 oncoprotein status by using molecular virology and immunohistochemistry methods. The prevalence of HPV16 infection was 22/41 (53.7%) and 20/31 (64.5%) for LSCC and HPSCC, accordingly. The majority of HPV16+ tumor samples were stage III or IV. In most samples, the presence of either HPV16 E6 or HPV16 E7 viral protein in dysplastic or tumor cells was confirmed using immunohistochemistry. Our results suggest a high prevalence of HPV16 as a primary HR-HPV type in LSCC and HPSCC. The lack of HPV E6/E7 oncoproteins in some tumor samples may suggest either the absence of viral integration or the presence of other mechanisms of tumorigenesis. The utilization of p16 IHC as a surrogate marker of HR-HPV infection is impractical in LSCC and HPSCC.

scholarly journals Human Papillomavirus E7 Protein Deregulates Mitosis via an Association with Nuclear Mitotic Apparatus Protein 1

2008 ◽  
Vol 83 (4) ◽  
pp. 1700-1707 ◽  
Author(s):  
Christine L. Nguyen ◽  
Karl Münger
Keyword(s):  
Human Papillomavirus ◽  
High Risk ◽  
Mitotic Spindles ◽  
Mitotic Apparatus ◽  
Human Papillomavirus Type 16 ◽  
Hpv E6 ◽  
Hpv E7 ◽  
Nuclear Mitotic Apparatus ◽  
E6 And E7 ◽  
High Risk Hpv

ABSTRACT We previously observed that high-risk human papillomavirus type 16 (HPV16) E7 expression leads to the delocalization of dynein from mitotic spindles (C. L. Nguyen, M. E. McLaughlin-Drubin, and K. Munger, Cancer Res. 68:8715-8722, 2008). Here, we show that HPV16 E7 associates with nuclear mitotic apparatus protein 1 (NuMA) and that NuMA binding and the ability to induce dynein delocalization map to similar carboxyl-terminal sequences of E7. Additionally, we show that the delocalization of dynein from mitotic spindles by HPV16 E7 and the interaction between HPV16 E7 and NuMA correlate with the induction of defects in chromosome alignment during prometaphase even in cells with normal centrosome numbers. Furthermore, low-risk HPV6b and HPV11 E7s also associate with NuMA and also induce a similar mitotic defect. It is possible that the disruption of mitotic events by HPV E7, via targeting of the NuMA/dynein complex and potentially other NuMA-containing complexes, contributes to viral maintenance and propagation potentially through abrogating the differentiation program of the infected epithelium. Furthermore, in concert with activities specific to high-risk HPV E6 and E7, such as the inactivation of the p53 and pRB tumor suppressors, respectively, the disruption of the NuMA/dynein network may result in mitotic errors that would make an infected cell more prone to the accumulation of aneuploidy even in the absence of supernumerary centrosomes.

scholarly journals Nuclear Entry of High-Risk Human Papillomavirus Type 16 E6 Oncoprotein Occurs via Several Pathways

2003 ◽  
Vol 77 (4) ◽  
pp. 2330-2337 ◽  
Author(s):  
Lucia G. Le Roux ◽  
Junona Moroianu
Keyword(s):  
Human Papillomavirus ◽  
High Risk ◽  
Hela Cells ◽  
Nuclear Import ◽  
Cellular Transformation ◽  
Transformation Process ◽  
Host Cells ◽  
Hpv16 E6 ◽  
Human Papillomavirus Type 16 ◽  
E6 Oncoprotein

ABSTRACT The E6 oncoprotein of high-risk human papillomavirus type 16 (HPV16) interacts with several nuclear transcription factors and coactivators in addition to cytoplasmic proteins, suggesting that nuclear import of HPV16 E6 plays a role in the cellular transformation process. In this study we have investigated the nuclear import pathways of HPV16 E6 in digitonin-permeabilized HeLa cells. We found that HPV16 E6 interacted with the karyopherin (Kap) α2 adapter and could enter the nucleus via a classical Kap α2β1-mediated pathway. Interestingly, HPV16 E6 also interacted, via its basic nuclear localization signal (NLS) located at the C terminus, with both Kap β1 and Kap β2 import receptors. Binding of RanGTP to these Kap βs inhibited their interaction with HPV16 E6 NLS. In agreement with these binding data, nuclear import of the HPV16 E6 oncoprotein in digitonin-permeabilized HeLa cells could be mediated by either Kap β1 or Kap β2. Nuclear import via these pathways required RanGDP and was independent of GTP hydrolysis by Ran. Significantly, an E6R124G mutant had reduced nuclear import activity, and the E6 deletion mutant lacking 121KKQR124 was not imported into the nucleus. The data reveal that the HPV16 E6 oncoprotein interacts via its C-terminal NLS with several karyopherins and exploits these interactions to enter the nucleus of host cells via multiple pathways.

scholarly journals Complementation of a p300/CBP defective-binding mutant of adenovirus E1a by human papillomavirus E6 proteins

2002 ◽  
Vol 83 (4) ◽  
pp. 829-833 ◽  
Author(s):  
Agnieszka Bernat ◽  
Paola Massimi ◽  
Lawrence Banks
Keyword(s):  
Human Papillomavirus ◽  
High Risk ◽  
Cell Transformation ◽  
Deficient Mutant ◽  
Hpv 16 ◽  
Adenovirus E1a ◽  
Human Papillomavirus Type 16 ◽  
Hpv E6 ◽  
E6 Protein ◽  
Hpv 18

Previous studies have shown that the human papillomavirus type 16 (HPV-16) E6 protein binds to p300/CBP and abrogates its transcriptional co-activator function. However, there is little information on the biological consequences of this interaction and discrepancy as to whether the interaction is high-risk E6 specific or not. We performed a series of studies to compare the interactions of HPV-18 and HPV-11 E6 with p300, and showed that both high- and low- risk E6 proteins bind p300. In addition, using a transformation-deficient mutant of adenovirus E1a, which cannot interact with p300, we demonstrated that HPV-16, HPV-18 and, to a lesser extent, HPV-11 E6, can complement this mutant in cell transformation assays. In contrast, a mutant of HPV-16 E6 which does not bind p300 failed to rescue the E1a mutant. These results suggest that the E6–p300 interaction may be important for the ability of HPV E6 to contribute towards cell transformation.

scholarly journals Identification and characterization of enhancer agonist human cytotoxic T-cell epitopes of the human papillomavirus type 16 (HPV16) E6/E7

Vaccine ◽  
2017 ◽  
Vol 35 (19) ◽  
pp. 2605-2611 ◽  
Author(s):  
Kwong Y. Tsang ◽  
Massimo Fantini ◽  
Romaine I. Fernando ◽  
Claudia Palena ◽  
Justin M. David ◽  
...  
Keyword(s):  
Human Papillomavirus ◽  
T Cell ◽  
Cytotoxic T Cell ◽  
T Cell Epitopes ◽  
Hpv16 E6 ◽  
Human Papillomavirus Type 16 ◽  
Identification And Characterization

scholarly journals PDZRN3/LNX3 Is a Novel Target of Human Papillomavirus Type 16 (HPV-16) and HPV-18 E6

2014 ◽  
Vol 89 (2) ◽  
pp. 1439-1444 ◽  
Author(s):  
Miranda Thomas ◽  
Lawrence Banks
Keyword(s):  
Human Papillomavirus ◽  
Binding Motif ◽  
Dependent Manner ◽  
Hpv 16 ◽  
Cellular Targets ◽  
Ubiquitin Protein Ligase ◽  
Human Papillomavirus Type 16 ◽  
Hpv E6 ◽  
Novel Target ◽  
Hpv 18

High-risk human papillomavirus (HPV) E6 proteins have a C-terminal PDZ binding motif through which they bind, and target for proteasome-mediated degradation, a number of PDZ-containing cellular targets. Recent studies have suggested that the RING-containing ubiquitin-protein ligase PDZRN3 might also be an HPV E6 target. In this analysis, we show that HPV-16 and HPV-18 E6 can target PDZRN3 in a PDZ- and proteasome-dependent manner and provide a connection between the HPV life cycle and differentiation-related STAT signaling.

A DNA vaccine based on a shuffled E7 oncogene of the human papillomavirus type 16 (HPV 16) induces E7-specific cytotoxic T cells but lacks transforming activity

Vaccine ◽  
2001 ◽  
Vol 19 (30) ◽  
pp. 4276-4286 ◽  
Author(s):  
Wolfram Osen ◽  
Tanja Peiler ◽  
Peter Öhlschläger ◽  
Sandra Caldeira ◽  
Stefan Faath ◽  
...  
Keyword(s):  
T Cells ◽  
Human Papillomavirus ◽  
Dna Vaccine ◽  
Cytotoxic T Cells ◽  
Hpv 16 ◽  
Human Papillomavirus Type 16 ◽  
Transforming Activity ◽  
E7 Oncogene

scholarly journals The E6 Oncoproteins of High-Risk Papillomaviruses Bind to a Novel Putative GAP Protein, E6TP1, and Target It for Degradation

1999 ◽  
Vol 19 (1) ◽  
pp. 733-744 ◽  
Author(s):  
Qingshen Gao ◽  
Seetha Srinivasan ◽  
Sarah N. Boyer ◽  
David E. Wazer ◽  
Vimla Band
Keyword(s):  
High Risk ◽  
P53 Protein ◽  
Single Gene ◽  
Human Papillomaviruses ◽  
Dominant Negative ◽  
Hpv16 E6 ◽  
Hpv E6 ◽  
E6 Oncoprotein ◽  
E6 Protein

ABSTRACT The high-risk human papillomaviruses (HPVs) are associated with carcinomas of the cervix and other genital tumors. Previous studies have identified two viral oncoproteins, E6 and E7, which are expressed in the majority of HPV-associated carcinomas. The ability of high-risk HPV E6 protein to immortalize human mammary epithelial cells (MECs) has provided a single-gene model to study the mechanisms of E6-induced oncogenic transformation. In this system, the E6 protein targets the p53 tumor suppressor protein for degradation, and mutational analyses have shown that E6-induced degradation of p53 protein is required for MEC immortalization. However, the inability of most dominant-negative p53 mutants to induce efficient immortalization of MECs suggests the existence of additional targets of the HPV E6 oncoprotein. Using the yeast two-hybrid system, we have isolated a novel E6-binding protein. This polypeptide, designated E6TP1 (E6-targeted protein 1), exhibits high homology to GTPase-activating proteins for Rap, including SPA-1, tuberin, and Rap1GAP. The mRNA for E6TP1 is widely expressed in tissues and in vitro-cultured cell lines. The gene for E6TP1 localizes to chromosome 14q23.2-14q24.3 within a locus that has been shown to undergo loss of heterozygosity in malignant meningiomas. Importantly, E6TP1 is targeted for degradation by the high-risk but not the low-risk HPV E6 proteins both in vitro and in vivo. Furthermore, the immortalization-competent but not the immortalization-incompetent HPV16 E6 mutants target the E6TP1 protein for degradation. Our results identify a novel target for the E6 oncoprotein and provide a potential link between HPV E6 oncogenesis and alteration of a small G protein signaling pathway.

Interaction of small G protein signaling modulator 3 with connexin 43 contributes to myocardial infarction in rat hearts

2017 ◽  
Vol 491 (2) ◽  
pp. 429-435 ◽  
Author(s):  
Chang Youn Lee ◽  
Jung-Won Choi ◽  
Sunhye Shin ◽  
Jiyun Lee ◽  
Hyang-Hee Seo ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
G Protein ◽  
Connexin 43 ◽  
G Protein Signaling ◽  
Protein Signaling ◽  
Small G Protein ◽  
Rat Hearts

scholarly journals NFX1 Plays a Role in Human Papillomavirus Type 16 E6 Activation of NFκB Activity

2010 ◽  
Vol 84 (21) ◽  
pp. 11461-11469 ◽  
Author(s):  
Mei Xu ◽  
Rachel A. Katzenellenbogen ◽  
Carla Grandori ◽  
Denise A. Galloway
Keyword(s):  
Human Papillomavirus ◽  
Human Telomerase Reverse Transcriptase ◽  
Hpv16 E6 ◽  
Regulatory Pathways ◽  
Cellular Processes ◽  
Hpv E6 ◽  
Host Cell Interactions ◽  
Nfκb Pathway ◽  
Human Telomerase ◽  
Dual Regulator

ABSTRACT High-risk human papillomavirus (HR HPV) requires differentiating epithelial cells to continue to divide in order to replicate the viral DNA. To achieve this, HPV perturbs several regulatory pathways, including cellular apoptosis and senescence signals. HPV E6 has been identified as a regulator of the NFκB signaling pathway, a pathway important in many cellular processes, as well as regulation of virus-host cell interactions. We report here that NFX1-91, an endogenously expressed transcriptional regulator of human telomerase reverse transcriptase (hTERT) that is targeted by HPV type 16 (HPV16) E6/E6-associated protein (E6AP) for degradation, is also critical for regulation of the NFκB pathway by HPV16 E6. Microarray analysis revealed induction of NFκB-responsive genes and reduction of NFκB inhibitors with knockdown of NFX1-91. Knockdown of NFX1-91 induced downregulation of p105, an NFκB inhibitor in both primary human foreskin keratinocytes (HFKs) and HCT116 cells. Chromatin immunoprecipitation assays further confirmed that NFX1-91 bound to the p105 promoter and upregulated its expression. Similarly, in HPV16 E6-positive cells, reduction of p105 expression was observed, paralleling knockdown of NFX1-91 expression. Overall, our data suggest a mechanism for HPV16 E6 activation of the NFκB pathway through NFX1-91. Also, it provides evidence that NFX1-91 can function as a dual regulator, not only a transcriptional repressor, but also a transcriptional activator, when bound to DNA.

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