scholarly journals The Interaction between Human Papillomavirus Type 16 and FADD Is Mediated by a Novel E6 Binding Domain

2008 ◽  
Vol 82 (19) ◽  
pp. 9600-9614 ◽  
Author(s):  
Sandy S. Tungteakkhun ◽  
Maria Filippova ◽  
Jonathan W. Neidigh ◽  
Nadja Fodor ◽  
Penelope J. Duerksen-Hughes
Keyword(s):  
Cervical Cancer ◽  
Human Papillomavirus ◽  
Tumor Necrosis Factor Receptor ◽  
Binding Domain ◽  
Death Domain ◽  
Infected Cells ◽  
E6 And E7 ◽  
Cancer Tissues

ABSTRACT High-risk strains of human papillomavirus, such as types 16 and 18, have been etiologically linked to cervical cancer. Most cervical cancer tissues are positive for both the E6 and E7 oncoproteins, since it is their cooperation that results in successful transformation and immortalization of infected cells. We have reported that E6 binds to tumor necrosis factor receptor 1 and to Fas-associated death domain (FADD) and, in doing so, prevents E6-expressing cells from responding to apoptotic stimuli. The binding site of E6 to FADD localizes to the first 23 amino acids of FADD and has now been further characterized by the use of deletion and site-directed mutants of FADD in pull-down and functional assays. The results from these experiments revealed that mutations of serine 16, serine 18, and leucine 20 obstruct FADD binding to E6, suggesting that these residues are part of the E6 binding domain on FADD. Because FADD does not contain the two previously identified E6 binding motifs, the LxxφLsh motif, and the PDZ motif, a novel binding domain for E6 has been identified on FADD. Furthermore, peptides that correspond to this region can block E6/FADD binding in vitro and can resensitize E6-expressing cells to apoptotic stimuli in vivo. These results demonstrate the existence of a novel E6 binding domain.

scholarly journals HPV-18 E6 Oncoprotein and Its Spliced Isoform E6*I Regulate the Wnt/β-Catenin Cell Signaling Pathway through the TCF-4 Transcriptional Factor

2018 ◽  
Vol 19 (10) ◽  
pp. 3153 ◽  
Author(s):  
J. Muñoz-Bello ◽  
Leslie Olmedo-Nieva ◽  
Leonardo Castro-Muñoz ◽  
Joaquín Manzo-Merino ◽  
Adriana Contreras-Paredes ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cell Proliferation ◽  
Signaling Pathway ◽  
Transcriptional Activation ◽  
Target Genes ◽  
Promote Cell Proliferation ◽  
E6 And E7 ◽  
Hpv 18

The Wnt/β-catenin signaling pathway regulates cell proliferation and differentiation and its aberrant activation in cervical cancer has been described. Persistent infection with high risk human papillomavirus (HR-HPV) is the most important factor for the development of this neoplasia, since E6 and E7 viral oncoproteins alter cellular processes, promoting cervical cancer development. A role of HPV-16 E6 in Wnt/β-catenin signaling has been proposed, although the participation of HPV-18 E6 has not been previously studied. The aim of this work was to investigate the participation of HPV-18 E6 and E6*I, in the regulation of the Wnt/β-catenin signaling pathway. Here, we show that E6 proteins up-regulate TCF-4 transcriptional activity and promote overexpression of Wnt target genes. In addition, it was demonstrated that E6 and E6*I bind to the TCF-4 (T cell factor 4) and β-catenin, impacting TCF-4 stabilization. We found that both E6 and E6*I proteins interact with the promoter of Sp5, in vitro and in vivo. Moreover, although differences in TCF-4 transcriptional activation were found among E6 intratype variants, no changes were observed in the levels of regulated genes. Furthermore, our data support that E6 proteins cooperate with β-catenin to promote cell proliferation.

scholarly journals Downregulation of TNF-α/TNF-R1 Signals by AT-Lipoxin A4 May Be a Significant Mechanism of Attenuation in SAP-Associated Lung Injury

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Suhui Yu ◽  
Jianming Xie ◽  
Yukai Xiang ◽  
Shengjie Dai ◽  
Dinglai Yu ◽  
...  
Keyword(s):  
Lung Injury ◽  
Tumor Necrosis Factor Receptor ◽  
Microvascular Endothelial Cell ◽  
Death Domain ◽  
Lipoxin A4 ◽  
Proinflammatory Mediators ◽  
Anti Inflammatory ◽  
Significant Mechanism

Our previous studies verified the potent anti-inflammatory effects against severe acute pancreatitis (SAP) of AT-Lipoxin A4 and their analogues. However, the anti-inflammatory effects of AT-Lipoxin A4 on SAP-associated lung injury are not thoroughly known. We used western blot, polymerase chain reaction (PCR), and immunofluorescence to investigate the downregulation of TNF-α signals in cellular and animal models of SAP-associated lung injury following AT-Lipoxin A4 intervention. In vitro, we found that AT-Lipoxin A4 markedly suppressed protein expression in TNF-α signals in human pulmonary microvascular endothelial cell, such as tumor necrosis factor receptor-associated factor 2 (TRAF2), TNF-R1-associated death domain (TRADD), receptor-interacting protein (RIP), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin. Moreover, AT-Lipoxin A4 inhibited downstream signals activated by TNF-α, including NF-κB/p65, JNK/MAPK, and ERK/MAPK. In vivo, AT-Lipoxin A4 significantly decreased pathological scores of the pancreas and lungs and the serum levels of IL-6 and TNF-α. Immunofluorescence, western blotting, and real-time PCR assay showed that AT-Lipoxin A4 significantly attenuated the expression of TNF-R1, TRADD, TRAF2, and RIP in the lungs of SAP rats. In addition, the activation of NF-κB was also downregulated by AT-Lipoxin A4 administration as compared with SAP rats. AT-Lipoxin A4 could inhibit the production of proinflammatory mediators and activation of TNF-α downstream signals such as NF-κB and MAPK. Downregulation of TNF-α signals by AT-Lipoxin A4 may be a significant mechanism in the attenuation of SAP-associated lung injury.

scholarly journals Bioinformatics Prediction of miRNAs Targeting E6 and E7 Genes in Human Papillomavirus Types 16 and 18 in Cervical Cancer

2020 ◽  
Vol 23 (3) ◽  
pp. 374-385
Author(s):  
Tahere Azimi ◽  
◽  
Malihe Bagheri ◽  
Mahdi Pariyan ◽  
Behzad Khansarinejad ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Human Papillomavirus ◽  
Early Stage ◽  
Medical Sciences ◽  
Ethical Considerations ◽  
E7 Gene ◽  
Bioinformatics Databases ◽  
E6 And E7 ◽  
New Biomarkers

Background and Aim: Cervical Cancer (CC) is the third most common malignancy in the women, the main cause of which is human papillomavirus (HPV). Both E6 and E7 oncogenes of the virus play an important role in its tumorigenesis. Today, methods available for screening CC are not capable of detecting the disease at an early stage. Therefore, it is important to identify new biomarkers for early detection of this cancer. For this purpose, in the present study, miRNAs targeting the two oncogenes E6 and E7 of human papillomavirus (types 16 and 18) were studied in CC by bioinformatics. Methods & Materials: First, using the NCBI database, the E6 and E7 gene sequences were obtained for both human papillomavirus types 16 and 18. Then, using the miRBase and RNA22 bioinformatics databases, the most appropriate targeting miRNAs for these genes were selected. Ethical Considerations: This study was approved by Ethics Committee of Arak University of Medical Sciences. Results: Based on the P obtained from bioinformatics databases, miRNA including miR-92a-5p (P=7.51e-2), miR-195-3p (P=2.24e-1), miR-34a-5p (P=2.73e-1) and miR-155-5p (P=4.95e-2) were introduced for the two genes E6 and E7. Conclusion: Results from bioinformatics studies revealed that of the four miRNAs identified, miR-155-5p and miR-92a-5p are probably the targeting miRNAs specific for the E6 and E7 genes, respectively. Therefore, it seems that these miRNAs can be a suitable candidate for in vitro studies in CC patients.

scholarly journals ST3Gal IV Mediates the Growth and Proliferation of Cervical Cancer Cells In Vitro and In Vivo Via the Notch/p21/CDKs Pathway

2021 ◽  
Vol 10 ◽  
Author(s):  
Yinshuang Wu ◽  
Xixi Chen ◽  
Weijie Dong ◽  
Zhongyang Xu ◽  
Yuli Jian ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Notch Pathway ◽  
Cell Cycle Protein ◽  
Cyclin E1 ◽  
Normal Cervix ◽  
Cervical Cancer Cells ◽  
Negative Role ◽  
Cancer Tissues

ST3Gal IV is one of the principal sialyltransferases responsible for the biosynthesis of α2, 3-sialic acid to the termini N-glycans or O-glycans of glycoproteins and glycolipids. It has been reported that ST3Gal IV expression is associated with gastric carcinoma, pancreatic adenocarcinoma and breast cancer. While the expression and functions of ST3Gal IV in cervical cancer are still poorly understood. In this study, we found that ST3Gal IV was downregulated in human cervical cancer tissues compared to normal cervix tissues, and ST3Gal IV expression was negatively associated with the pathological grade of cervical cancer. ST3Gal IV upregulation inhibited the growth and proliferation of cervical cancer HeLa and SiHa cells in vitro and in vivo. Furthermore, ST3Gal IV overexpression enhanced the expression of several Notch pathway components such as Jagged1, Notch1, Hes1 and Hey1, while cell cycle protein expression like Cyclin D1, Cyclin E1, CDK2 and CDK4 were decreased. These results indicate that expression of ST3Gal IV is reduced in cervical cancer and plays a negative role in cell proliferation via Notch/p21/CDKs signaling pathway. Thus, sialyltransferase ST3Gal IV might be a target for the diagnosis and therapy of cervical cancer.

scholarly journals In vitro and in vivo growth suppression of human papillomavirus 16-positive cervical cancer cells by e6 siRNA

2003 ◽  
Vol 8 (5) ◽  
pp. 762-768 ◽  
Author(s):  
Mitsuo Yoshinouchi ◽  
Taketo Yamada ◽  
Masahiro Kizaki ◽  
Jin Fen ◽  
Takeyoshi Koseki ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Human Papillomavirus ◽  
Cancer Cells ◽  
Growth Suppression ◽  
Human Papillomavirus 16 ◽  
Cervical Cancer Cells ◽  
In Vivo Growth
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