The HPV16 E6 oncoprotein and UVB irradiation inhibit the tumor suppressor TGFβ pathway in the epidermis of the K14E6 transgenic mouse

2015 ◽  
Vol 24 (6) ◽  
pp. 430-435 ◽  
Author(s):  
Marco Popoca-Cuaya ◽  
Jose Diaz-Chavez ◽  
Jesus Hernandez-Monge ◽  
Elizabeth Alvarez-Rios ◽  
Paul F. Lambert ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Transgenic Mouse ◽  
Hpv16 E6 ◽  
Uvb Irradiation ◽  
E6 Oncoprotein ◽  
Tgfβ Pathway

scholarly journals HPV16-E6 Oncoprotein Activates TGF-βand Wnt/β-Catenin Pathways in the Epithelium-Mesenchymal Transition of Cataracts in a Transgenic Mouse Model

2018 ◽  
Vol 2018 ◽  
pp. 1-17
Author(s):  
Genaro Rodríguez-Uribe ◽  
Nicolas Serafín-Higuera ◽  
Gabriela Damian-Morales ◽  
Enoc Mariano Cortés-Malagón ◽  
Vicky García-Hernández ◽  
...  
Keyword(s):  
Transgenic Mouse ◽  
Transgenic Mouse Model ◽  
Rt Pcr ◽  
Hpv16 E6 ◽  
Mesenchymal Transition ◽  
Protein Levels ◽  
E6 Oncoprotein ◽  
Signaling Activation ◽  
Smad7 Protein

Objective. This work aimed to determine if cataractous changes associated with EMT occurring in the K14E6 mice lenses are associated with TGF-βand Wnt/β-catenin signaling activation.Materials and Methods. Cataracts of K14E6 mice were analysed histologically; and components of TGF-βand Wnt/β-catenin signaling were evaluated by Western blot, RT-qPCR, in situ RT-PCR, IHC, or IF technics. Metalloproteinases involved in EMT were also assayed using zymography. The endogenous stabilisation of Smad7 protein was also assessed using an HDAC inhibitor.Results. The K14E6 mice, which displayed binocular cataracts in 100% of the animals, exhibited loss of tissue organisation, cortical liquefaction, and an increase in the number of hyperproliferative-nucleated cells with mesenchymal-like characteristics in the lenses. Changes in lenses’ cell morphology were due to actin filaments reorganisation, activation of TGF-βand Wnt/β-catenin pathways, and the accumulation of MTA1 protein. Finally, the stabilisation of Smad7 protein diminishes cell proliferation, as well as MTA1 protein levels.Conclusion. The HPV16-E6 oncoprotein induces EMT in transgenic mice cataracts. The molecular mechanism may involve TGF-βand Wnt/β-catenin pathways, suggesting that the K14E6 transgenic mouse could be a useful model for the study or treatment of EMT-induced cataracts.

scholarly journals KDM6A mediated expression of the long noncoding RNA DINO causes TP53 tumor suppressor stabilization in Human Papillomavirus type 16 E7 expressing cells

2020 ◽  
Author(s):  
Surendra Sharma ◽  
Karl Munger
Keyword(s):  
Cell Death ◽  
Tumor Suppressor ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Critical Role ◽  
Metabolic Stress ◽  
Dominant Negative ◽  
Missing Link ◽  
Hpv16 E6 ◽  
E6 And E7

ABSTRACTHPV16 E7 has long been noted to stabilize the TP53 tumor suppressor. However, the molecular mechanism of TP53 stabilization by HPV16 E7 has remained obscure and can occur independent of E2F regulated MDM2 inhibitor, p14ARF. Here, we report that the Damage Induced Noncoding (DINO) lncRNA (DINOL) is the missing link between HPV16 E7 and increased TP53 levels. DINO levels are decreased in cells where TP53 is inactivated, either by HPV16 E6, expression of a dominant negative TP53 minigene or by TP53 depletion. DINO levels are increased in HPV16 E7 expressing cells. HPV16 E7 causes increased DINO expression independent of RB1 degradation and E2F1 activation. Similar to the adjacent CDKN1A locus, DINO expression is regulated by the histone demethylase, KDM6A. DINO stabilizes TP53 in HPV16 E7 expressing cells and as a TP53 transcriptional target, DINO levels further increase. Similar to other oncogenes such as adenovirus E1A or MYC, HPV16 E7 expressing cells are sensitized to cell death under conditions of metabolic stress and in the case of E7, this has been linked to TP53 activation. Consistent with earlier studies, we show that HPV16 E7 expressing keratinocytes are highly sensitive to metabolic stress induced by the antidiabetic drug, metformin. Metformin sensitivity of HPV16 E7 expressing cells is rescued by DINO depletion. This work identifies DINO as a critical mediator TP53 stabilization and activation in HPV16 E7 expressing cells.IMPORTANCEViral oncoproteins, including HPV16 E6 and E7 have been instrumental in elucidating the activities of cellular signaling networks including those governed by the TP53 tumor suppressor. Our study demonstrates that the long noncoding RNA DINO is the long sought missing link between HPV16 E7 and elevated TP53 levels. Importantly, the TP53 stabilizing DINO plays a critical role in the predisposition of HPV16 E7 expressing cells to cell death under metabolic stress conditions from metformin treatment.

scholarly journals HPV16 E6 oncoprotein‐induced upregulation of lncRNA GABPB1‐AS1 facilitates cervical cancer progression by regulating miR‐519e‐5p/Notch2 axis

2020 ◽  
Vol 34 (10) ◽  
pp. 13211-13223
Author(s):  
Rongying Ou ◽  
Mingfen Lv ◽  
Xuan Liu ◽  
Jiangmin Lv ◽  
Jinduo Zhao ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cancer Progression ◽  
Hpv16 E6 ◽  
E6 Oncoprotein

scholarly journals Solution Structure Analysis of the HPV16 E6 Oncoprotein Reveals a Self-Association Mechanism Required for E6-Mediated Degradation of p53

Structure ◽  
2012 ◽  
Vol 20 (4) ◽  
pp. 604-617 ◽  
Author(s):  
Katia Zanier ◽  
Abdellahi ould M'hamed ould Sidi ◽  
Charlotte Boulade-Ladame ◽  
Vladimir Rybin ◽  
Anne Chappelle ◽  
...  
Keyword(s):  
Structure Analysis ◽  
Solution Structure ◽  
Hpv16 E6 ◽  
E6 Oncoprotein ◽  
Self Association

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.

Defining the minimal interacting regions of the tight junction protein MAGI-1 and HPV16 E6 oncoprotein for solution structure studies

2008 ◽  
Vol 60 (1) ◽  
pp. 64-73 ◽  
Author(s):  
Sebastian Charbonnier ◽  
Gunter Stier ◽  
Georges Orfanoudakis ◽  
Bruno Kieffer ◽  
R. Andrew Atkinson ◽  
...  
Keyword(s):  
Tight Junction ◽  
Solution Structure ◽  
Tight Junction Protein ◽  
Hpv16 E6 ◽  
E6 Oncoprotein ◽  
Junction Protein

HPV16 E6 oncoprotein increases cell adhesion in human keratinocytes

2008 ◽  
Vol 154 (1) ◽  
pp. 55-63 ◽  
Author(s):  
Alexander Epshtein ◽  
A. Jackman ◽  
P. Gonen ◽  
L. Sherman
Keyword(s):  
Cell Adhesion ◽  
Human Keratinocytes ◽  
Hpv16 E6 ◽  
E6 Oncoprotein

scholarly journals Inhibition of Serum- and Calcium-Induced Differentiation of Human Keratinocytes by HPV16 E6 Oncoprotein: Role of p53 Inactivation

Virology ◽  
1997 ◽  
Vol 237 (2) ◽  
pp. 296-306 ◽  
Author(s):  
Levana Sherman ◽  
Anna Jackman ◽  
Hagar Itzhaki ◽  
Melissa Conrad Stöppler ◽  
Debbie Koval ◽  
...  
Keyword(s):  
Human Keratinocytes ◽  
Induced Differentiation ◽  
Hpv16 E6 ◽  
E6 Oncoprotein ◽  
P53 Inactivation
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