scholarly journals HPV Oncoproteins and the Ubiquitin Proteasome System: A Signature of Malignancy?

Pathogens ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 133 ◽  
Author(s):  
Anamaria Đukić ◽  
Lucija Lulić ◽  
Miranda Thomas ◽  
Josipa Skelin ◽  
Nathaniel Edward Bennett Saidu ◽  
...  
Keyword(s):  
Ubiquitin Proteasome System ◽  
Cellular Functions ◽  
Hpv E6 ◽  
System A ◽  
Ubiquitin Proteasome ◽  
Cellular Pathways ◽  
E6 And E7 Oncoproteins ◽  
E6 And E7 ◽  
Hpv Oncoproteins ◽  
Regulation Of Cell Cycle

Human papillomavirus (HPV) E6 and E7 oncoproteins are critical for development and maintenance of the malignant phenotype in HPV-induced cancers. These two viral oncoproteins interfere with a plethora of cellular pathways, including the regulation of cell cycle and the control of apoptosis, which are critical in maintaining normal cellular functions. E6 and E7 bind directly with certain components of the Ubiquitin Proteasome System (UPS), enabling them to manipulate a number of important cellular pathways. These activities are the means by which HPV establishes an environment supporting the normal viral life cycle, however in some instances they can also lead to the development of malignancy. In this review, we have discussed how E6 and E7 oncoproteins from alpha and beta HPV types interact with the components of the UPS, and how this interplay contributes to the development of cancer.

scholarly journals Mapping the interactome of HPV E6 and E7 oncoproteins with the ubiquitin-proteasome system

FEBS Journal ◽  
2017 ◽  
Vol 284 (19) ◽  
pp. 3171-3201 ◽  
Author(s):  
Juline Poirson ◽  
Elise Biquand ◽  
Marie-Laure Straub ◽  
Patricia Cassonnet ◽  
Yves Nominé ◽  
...  
Keyword(s):  
Ubiquitin Proteasome System ◽  
Hpv E6 ◽  
Ubiquitin Proteasome ◽  
E6 And E7 Oncoproteins ◽  
E6 And E7

scholarly journals Advances in Deubiquitinating Enzyme Inhibition and Applications in Cancer Therapeutics

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1579 ◽  
Author(s):  
Ainsley Mike Antao ◽  
Apoorvi Tyagi ◽  
Kye-Seong Kim ◽  
Suresh Ramakrishna
Keyword(s):  
Protein Interactions ◽  
Cancer Therapeutics ◽  
Ubiquitin Proteasome System ◽  
Deubiquitinating Enzyme ◽  
Protein Protein Interactions ◽  
Deubiquitinating Enzymes ◽  
Cellular Functions ◽  
E3 Ligases ◽  
Ubiquitin Proteasome ◽  
Target Cancer

Since the discovery of the ubiquitin proteasome system (UPS), the roles of ubiquitinating and deubiquitinating enzymes (DUBs) have been widely elucidated. The ubiquitination of proteins regulates many aspects of cellular functions such as protein degradation and localization, and also modifies protein-protein interactions. DUBs cleave the attached ubiquitin moieties from substrates and thereby reverse the process of ubiquitination. The dysregulation of these two paramount pathways has been implicated in numerous diseases, including cancer. Attempts are being made to identify inhibitors of ubiquitin E3 ligases and DUBs that potentially have clinical implications in cancer, making them an important target in the pharmaceutical industry. Therefore, studies in medicine are currently focused on the pharmacological disruption of DUB activity as a rationale to specifically target cancer-causing protein aberrations. Here, we briefly discuss the pathophysiological and physiological roles of DUBs in key cancer-related pathways. We also discuss the clinical applications of promising DUB inhibitors that may contribute to the development of DUBs as key therapeutic targets in the future.

scholarly journals Upregulation of PIR gene expression induced by human papillomavirus E6 and E7 in epithelial oral and cervical cells

Open Biology ◽  
2017 ◽  
Vol 7 (11) ◽  
pp. 170111 ◽  
Author(s):  
Diego Carrillo ◽  
Juan P. Muñoz ◽  
Hernán Huerta ◽  
Gabriel Leal ◽  
Alejandro Corvalán ◽  
...  
Keyword(s):  
Gene Expression ◽  
Human Papillomavirus ◽  
Dna Microarrays ◽  
Epithelial Mesenchymal Transition ◽  
Dependent Manner ◽  
Mesenchymal Transition ◽  
Hpv E6 ◽  
E6 And E7 Oncoproteins ◽  
E6 And E7 ◽  
Oral Cells

The hallmark of high-risk human papillomavirus (HR-HPV)-related carcinogenesis is E6 and E7 oncogene overexpression. The aim of this work was to characterize epithelial oral and cervical cancer cells that express HR-HPV E6 and E7 oncoproteins. Transcriptomic assay using DNA microarrays revealed that PIR gene expression was detected in oral cells in an HR-HPV E6/E7-dependent manner. In addition, PIR was overexpressed in HPV-positive SiHa and Ca Ski cells, whereas it was undetectable in HPV-negative C33A cells. The PIR expression was dependent on functional HR-HPV E6 and E7 oncoproteins even though the E7 oncoprotein had higher activity to induce PIR overexpression in comparison with E6. In addition, using an siRNA for PIR silencing in oral cells ectopically expressing HR-HPV E6/E7, there was a significant increase in E-cadherin transcripts and a decrease in Vimentin, Slug, Zeb and Snail transcripts, suggesting that HR-HPV-induced PIR overexpression is involved in epithelial–mesenchymal transition. Furthermore, migration of PIR-silenced cells was significantly decreased. Finally, using inhibitors of some specific pathways, it was found that EGFR/ERK and PI3 K/AKT signalling pathways are important for E7-mediated PIR overexpression. It can be concluded that PIR gene expression is highly dependent on the expression of HR-HPV oncoproteins and is important for EMT regulation.

scholarly journals Generalizable Compositional Features Influencing the Proteostatic Fates of Polar Low-Complexity Domains

2021 ◽  
Vol 22 (16) ◽  
pp. 8944
Author(s):  
Sean M. Cascarina ◽  
Joshua P. Kaplan ◽  
Mikaela R. Elder ◽  
Lindsey Brookbank ◽  
Eric D. Ross
Keyword(s):  
Protein Aggregation ◽  
Ubiquitin Proteasome System ◽  
Low Complexity ◽  
Hydrophobic Residues ◽  
System A ◽  
Polar Low ◽  
Eukaryotic Proteomes ◽  
Ubiquitin Proteasome ◽  
Folded Proteins ◽  
Aggregation Activity

Protein aggregation is associated with a growing list of human diseases. A substantial fraction of proteins in eukaryotic proteomes constitutes a proteostasis network—a collection of proteins that work together to maintain properly folded proteins. One of the overarching functions of the proteostasis network is the prevention or reversal of protein aggregation. How proteins aggregate in spite of the anti-aggregation activity of the proteostasis machinery is incompletely understood. Exposed hydrophobic patches can trigger degradation by the ubiquitin-proteasome system, a key branch of the proteostasis network. However, in a recent study, we found that model glycine (G)-rich or glutamine/asparagine (Q/N)-rich prion-like domains differ in their susceptibility to detection and degradation by this system. Here, we expand upon this work by examining whether the features controlling the degradation of our model prion-like domains generalize broadly to G-rich and Q/N-rich domains. Experimentally, native yeast G-rich domains in isolation are sensitive to the degradation-promoting effects of hydrophobic residues, whereas native Q/N-rich domains completely resist these effects and tend to aggregate instead. Bioinformatic analyses indicate that native G-rich domains from yeast and humans tend to avoid degradation-promoting features, suggesting that the proteostasis network may act as a form of selection at the molecular level that constrains the sequence space accessible to G-rich domains. However, the sensitivity or resistance of G-rich and Q/N-rich domains, respectively, was not always preserved in their native protein contexts, highlighting that proteins can evolve other sequence features to overcome the intrinsic sensitivity of some LCDs to degradation.

Targeting the Ubiquitin-proteasome System for the Treatment of Multiple Myeloma and Other Human Diseases

2010 ◽  
Vol 2 ◽  
pp. CMT.S2889
Author(s):  
Klaus Podar ◽  
Kenneth C. Anderson
Keyword(s):  
Multiple Myeloma ◽  
Proteasome Inhibitor ◽  
Ubiquitin Proteasome System ◽  
Hematologic Malignancies ◽  
Mechanisms Of Action ◽  
Human Diseases ◽  
Cellular Functions ◽  
Adverse Side Effects ◽  
Ubiquitin Proteasome ◽  
Novel Approaches

The ubiquitin-proteasome-degradation system plays a key role in multiple cellular functions. Its deregulation is associated with the initiation and progression of human diseases including not only solid and hematologic malignancies but also neurologic and autoimmune disorders. This article discusses several novel mechanistic aspects of the ubiquitin-proteasome system. Moreover, it focuses on the development, mechanisms of action, and clinical experience with Bortezomib, the first in-class-proteasome inhibitor to enter the clinics. Finally, it summarizes novel approaches to specifically target distinct components within the highly complex and dynamic ubiquitin-proteasome machinery to ultimately further increase drug activity, as well as reduce drug resistance and adverse side effects.

Targeting of host-cell ubiquitin pathways by viruses

2005 ◽  
Vol 41 ◽  
pp. 139-156 ◽  
Author(s):  
Julia Shackelford ◽  
Joseph S. Pagano
Keyword(s):  
Host Cell ◽  
Cell Biology ◽  
Cell Signalling ◽  
Ubiquitin Proteasome System ◽  
Life Cycles ◽  
Therapeutic Interventions ◽  
Signalling Pathways ◽  
Cellular Functions ◽  
Ubiquitin Proteasome ◽  
Do So

The ability of viruses to co-opt cell signalling pathways has, over millions of years of co-evolution, come to pervade nearly every facet of cellular functions. Recognition of the extent to which the ubiquitin–proteasome system can be directed or subverted by viruses is relatively recent. Viral products interact with, and adjust, the ubiquitin–proteasome machinery precisely and at many levels, and they do so at distinct stages of viral life-cycles. The implications for both cells and viruses are fundamental, and understanding viral strategies in this context opens up fascinating new areas for research that span from basic cell biology to therapeutic interventions against both viruses and malignancies.

scholarly journals Manipulation of Epithelial Differentiation by HPV Oncoproteins

Viruses ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 369 ◽  
Author(s):  
Elizabeth A. White
Keyword(s):  
Hpv Infection ◽  
Epithelial Differentiation ◽  
Inhibitory Mechanisms ◽  
Open Questions ◽  
Key Features ◽  
E6 And E7 Oncoproteins ◽  
E6 And E7 ◽  
Hpv Oncoproteins ◽  
The Relationship ◽  
Do So

Papillomaviruses replicate and cause disease in stratified squamous epithelia. Epithelial differentiation is essential for the progression of papillomavirus replication, but differentiation is also impaired by papillomavirus-encoded proteins. The papillomavirus E6 and E7 oncoproteins partially inhibit and/or delay epithelial differentiation and some of the mechanisms by which they do so are beginning to be defined. This review will outline the key features of the relationship between HPV infection and differentiation and will summarize the data indicating that papillomaviruses alter epithelial differentiation. It will describe what is known so far and will highlight open questions about the differentiation-inhibitory mechanisms employed by the papillomaviruses.

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