scholarly journals Papillomavirus E7 Oncoproteins Share Functions with Polyomavirus Small T Antigens

2014 ◽  
Vol 89 (5) ◽  
pp. 2857-2865 ◽  
Author(s):  
Elizabeth A. White ◽  
Rebecca E. Kramer ◽  
Justin H. Hwang ◽  
Arun T. Pores Fernando ◽  
Nana Naetar ◽  
...  
Keyword(s):  
T Antigen ◽  
Human Papillomaviruses ◽  
T Antigens ◽  
Tumor Viruses ◽  
Murine Polyomavirus ◽  
Cellular Pathways ◽  
E6 And E7 Oncoproteins ◽  
E6 And E7 ◽  
Transforming Proteins ◽  
E7 Proteins

ABSTRACTMany of the small DNA tumor viruses encode transforming proteins that function by targeting critical cellular pathways involved in cell proliferation and survival. In this study, we have examined whether some of the functions of the polyomavirus small T antigens (ST) are shared by the E6 and E7 oncoproteins of two oncogenic papillomaviruses. Using three different assays, we have found that E7 can provide some simian virus 40 (SV40) or murine polyomavirus (PyV) ST functions. Both human papillomavirus 16 (HPV16) and bovine papillomavirus (BPV1) E7 proteins are capable of partially substituting for SV40 ST in a transformation assay that also includes SV40 large T antigen, the catalytic subunit of cellular telomerase, and oncogenic Ras. Like SV40 ST, HPV16 E7 has the ability to override a quiescence block induced by mitogen deprivation. Like PyV ST, it also has the ability to inhibit myoblast differentiation. At least two of these activities are dependent upon the interaction of HPV16 E7 with retinoblastoma protein family members. For small T antigens, interaction with PP2A is needed for each of these functions. Even though there is no strong evidence that E6 or E7 share the ability of small T to interact with PP2A, E7 provides these functions related to cellular transformation.IMPORTANCEDNA tumor viruses have provided major insights into how cancers develop. Some viruses, like the human papillomaviruses, can cause cancer directly. Both the papillomaviruses and the polyomaviruses have served as tools for understanding pathways that are often perturbed in cancer. Here, we have compared the functions of transforming proteins from several DNA tumor viruses, including two papillomaviruses and two polyomaviruses. We tested the papillomavirus E6 and E7 oncoproteins in three functional assays and found that E7 can provide some or all of the functions of the SV40 small T antigen, another well-characterized oncoprotein, in two of these assays. In a third assay, papillomavirus E7 has the same effect as the murine polyomavirus small T protein. In summary, we report several new functions for the papillomavirus E7 proteins, which will contribute new insights into the roles of viruses in cancer and the cellular pathways they perturb in carcinogenesis.

The biological properties of E6 and E7 oncoproteins from human papillomaviruses

Virus Genes ◽  
2009 ◽  
Vol 40 (1) ◽  
pp. 1-13 ◽  
Author(s):  
Raffaella Ghittoni ◽  
Rosita Accardi ◽  
Uzma Hasan ◽  
Tarik Gheit ◽  
Bakary Sylla ◽  
...  
Keyword(s):  
Biological Properties ◽  
Human Papillomaviruses ◽  
E6 And E7 Oncoproteins ◽  
E6 And E7

scholarly journals Suppression of MicroRNA 424 Levels by Human Papillomaviruses Is Necessary for Differentiation-Dependent Genome Amplification

2017 ◽  
Vol 91 (24) ◽  
Author(s):  
Shiyuan Hong ◽  
Shouqiang Cheng ◽  
William Songock ◽  
Jason Bodily ◽  
Laimonis A. Laimins
Keyword(s):  
Dna Damage ◽  
Critical Role ◽  
Human Papillomaviruses ◽  
Expression Vectors ◽  
Hpv E6 ◽  
Damage Repair ◽  
Undifferentiated Cells ◽  
Efficient Replication ◽  
E6 And E7 ◽  
E7 Proteins

ABSTRACT High-risk human papillomaviruses (HPVs) link their life cycle to epithelial differentiation and require activation of DNA damage pathways for efficient replication. HPVs modulate the expression of cellular transcription factors, as well as cellular microRNAs (miRNAs) to control these activities. One miRNA that has been reported to be repressed in HPV-positive cancers of the cervix and oropharynx is miR-424. Our studies show that miR-424 levels are suppressed in cell lines that stably maintain HPV 31 or 16 episomes, as well as cervical cancer lines that contain integrated genomes such as SiHa. Introduction of expression vectors for miR-424 reduced both the levels of HPV genomes in undifferentiated cells and amplification upon differentiation. Our studies show that the levels of two putative targets of miR-424 that function in DNA damage repair, CHK1 and Wee1, are suppressed in HPV-positive cells, providing an explanation for why this microRNA is targeted in HPV-positive cells. IMPORTANCE We describe here for the first time a critical role for miR-424 in the regulation of HPV replication. HPV E6 and E7 proteins suppress the levels of miR-424, and this is important for controlling the levels of CHK1, which plays a central role in viral replication.

scholarly journals Lessons in Signaling and Tumorigenesis from Polyomavirus Middle T Antigen

2009 ◽  
Vol 73 (3) ◽  
pp. 542-563 ◽  
Author(s):  
Michele M. Fluck ◽  
Brian S. Schaffhausen
Keyword(s):  
Breast Cancer ◽  
Life Cycle ◽  
Tumor Progression ◽  
T Antigen ◽  
Eukaryotic Cells ◽  
Tumor Viruses ◽  
Murine Polyomavirus ◽  
Polyomavirus Middle T Antigen ◽  
Middle T Antigen

SUMMARY The small DNA tumor viruses have provided a very long-lived source of insights into many aspects of the life cycle of eukaryotic cells. In recent years, the emphasis has been on cancer-related signaling. Here we review murine polyomavirus middle T antigen, its mechanisms, and its downstream pathways of transformation. We concentrate on the MMTV-PyMT transgenic mouse, one of the most studied models of breast cancer, which permits the examination of in situ tumor progression from hyperplasia to metastasis.

scholarly journals CRISPR/Cas9-based inactivation of human papillomavirus oncogenes E6 and E7 induces senescence in cervical cancer cells

2020 ◽  
Author(s):  
Raviteja Inturi ◽  
Per Jemth
Keyword(s):  
Cancer Cells ◽  
Cellular Senescence ◽  
Hela Cells ◽  
Human Papillomaviruses ◽  
Alternative Outcome ◽  
Cervical Cancer Cells ◽  
Nucleus Surface ◽  
Hpv18 E6 ◽  
E6 And E7 ◽  
E7 Proteins

ABSTRACTHuman papillomaviruses (HPVs) such as HPV16 and HPV18 can cause cancers of the cervix, vagina, vulva, penis, anus and oropharynx. Continuous expression of the HPV viral oncoproteins E6 and E7 are essential for transformation and maintenance of cancer cells. Therefore, therapeutic targeting of E6 and E7 genes can potentially be used to treat HPV-related cancers. Previous CRISPR/Cas9 studies on inactivation of E6 and E7 genes confirmed cell cycle arrest and apoptosis. Here we report that CRISPR/Cas9-based knockout of E6 and E7 can also trigger cellular senescence in HPV18 immortalized HeLa cells. Specifically, HeLa cells in which E6 and E7 were inactivated exhibited characteristic senescence markers like enlarged cell and nucleus surface area, increased β-galactosidase expression, and loss of lamin B1 with detection of cytoplasmic chromatin fragments. Furthermore, the knockout of HPV18 E6 and E7 proteins resulted in upregulation of p53/p21 and pRb/p21 levels in senescent cells. These senescent cells were devoid of characteristic apoptotic markers and re-introduction of codon-modified HPV18 E6 decreased p53 levels. Taken together, our study demonstrates that cellular senescence is as an alternative outcome of HPV oncogene inactivation by the CRISPR/Cas9 methodology.

scholarly journals Spindle assembly checkpoint signaling and sister chromatid cohesion are disrupted by HPV E6-mediated transformation

2017 ◽  
Vol 28 (15) ◽  
pp. 2035-2041 ◽  
Author(s):  
Hazheen K. Shirnekhi ◽  
Erin P. Kelley ◽  
Jennifer G. DeLuca ◽  
Jacob A. Herman
Keyword(s):  
Cancer Progression ◽  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Mitotic Exit ◽  
Human Papillomaviruses ◽  
Checkpoint Signaling ◽  
Hpv E6 ◽  
Chromatid Cohesion ◽  
E6 And E7 ◽  
Transforming Proteins

Aneuploidy, a condition that results from unequal partitioning of chromosomes during mitosis, is a hallmark of many cancers, including those caused by human papillomaviruses (HPVs). E6 and E7 are the primary transforming proteins in HPV that drive tumor progression. In this study, we stably expressed E6 and E7 in noncancerous RPE1 cells and analyzed the specific mitotic defects that contribute to aneuploidy in each cell line. We find that E6 expression results in multiple chromosomes associated with one or both spindle poles, causing a significant mitotic delay. In most cells, the misaligned chromosomes eventually migrated to the spindle equator, leading to mitotic exit. In some cells, however, mitotic exit occurred in the presence of pole-associated chromosomes. We determined that this premature mitotic exit is due to defects in spindle assembly checkpoint (SAC) signaling, such that cells are unable to maintain a prolonged mitotic arrest in the presence of unaligned chromosomes. This SAC defect is caused in part by a loss of kinetochore-associated Mad2 in E6-expressing cells. Our results demonstrate that E6-expressing cells exhibit previously unappreciated mitotic defects that likely contribute to HPV-mediated cancer progression.

scholarly journals The Major Constituent of Green Tea, Epigallocatechin-3-Gallate (EGCG), Inhibits the Growth of HPV18-Infected Keratinocytes by Stimulating Proteasomal Turnover of the E6 and E7 Oncoproteins

Pathogens ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 459
Author(s):  
Jason K. W. Yap ◽  
Sean T. Kehoe ◽  
Ciaran B. J. Woodman ◽  
Christopher W. Dawson
Keyword(s):  
Cell Proliferation ◽  
Green Tea ◽  
Keratinocyte Differentiation ◽  
Major Constituent ◽  
Tumour Suppressor Genes ◽  
Raft Culture ◽  
Egcg Treatment ◽  
E6 And E7 Oncoproteins ◽  
E6 And E7 ◽  
E7 Proteins

Epigallocatechin-3-gallate (EGCG), the primary bioactive polyphenol in green tea, has been shown to inhibit the growth of human papilloma virus (HPV)-transformed keratinocytes. Here, we set out to examine the consequences of EGCG treatment on the growth of HPV18-immortalised foreskin keratinocytes (HFK-HPV18) and an authentic HPV18-positive vulvar intraepithelial neoplasia (VIN) clone, focusing on its ability to influence cell proliferation and differentiation and to impact on viral oncogene expression and virus replication. EGCG treatment was associated with degradation of the E6 and E7 oncoproteins and an upregulation of their associated tumour suppressor genes; consequently, keratinocyte proliferation was inhibited in both monolayer and organotypic raft culture. While EGCG exerted a profound effect on cell proliferation, it had little impact on keratinocyte differentiation. Expression of the late viral protein E4 was suppressed in the presence of EGCG, suggesting that EGCG was able to block productive viral replication in differentiating keratinocytes. Although EGCG did not alter the levels of E6 and E7 mRNA, it enhanced the turnover of the E6 and E7 proteins. The addition of MG132, a proteasome inhibitor, to EGCG-treated keratinocytes led to the accumulation of the E6/E7 proteins, showing that EGCG acts as an anti-viral, targeting the E6 and E7 proteins for proteasome-mediated degradation.

scholarly journals The Role of Long Noncoding RNAs in Human Papillomavirus-associated Pathogenesis

Pathogens ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 289 ◽  
Author(s):  
Surendra Sharma ◽  
Karl Munger
Keyword(s):  
Human Papillomavirus ◽  
Noncoding Rnas ◽  
Human Papillomaviruses ◽  
Long Noncoding Rnas ◽  
Protein Targets ◽  
Hpv E6 ◽  
Small Proteins ◽  
E6 And E7 ◽  
E7 Proteins

Infections with high-risk human papillomaviruses cause ~5% of all human cancers. E6 and E7 are the only viral genes that are consistently expressed in cancers, and they are necessary for tumor initiation, progression, and maintenance. E6 and E7 encode small proteins that lack intrinsic enzymatic activities and they function by binding to cellular regulatory molecules, thereby subverting normal cellular homeostasis. Much effort has focused on identifying protein targets of the E6 and E7 proteins, but it has been estimated that ~98% of the human transcriptome does not encode proteins. There is a growing interest in studying noncoding RNAs as biochemical targets and biological mediators of human papillomavirus (HPV) E6/E7 oncogenic activities. This review focuses on HPV E6/E7 targeting cellular long noncoding RNAs, a class of biologically versatile molecules that regulate almost every known biological process and how this may contribute to viral oncogenesis.

scholarly journals Origin and evolution of papillomavirus (onco)genes and genomes

2019 ◽  
Vol 374 (1773) ◽  
pp. 20180303 ◽  
Author(s):  
Anouk Willemsen ◽  
Ignacio G. Bravo
Keyword(s):  
Common Ancestor ◽  
Current Knowledge ◽  
Phylogenetic Analyses ◽  
Genotypic Diversity ◽  
Human Papillomaviruses ◽  
Recent Common Ancestor ◽  
Origin And Evolution ◽  
Most Recent Common Ancestor ◽  
E6 And E7 ◽  
E7 Proteins

Papillomaviruses (PVs) are ancient viruses infecting vertebrates, from fishes to mammals. Although the genomes of PVs are small and show conserved synteny, PVs display large genotypic diversity and ample variation in the phenotypic presentation of the infection. Most PV genomes contain two small early genes E6 and E7 . In a bunch of closely related human papillomaviruses (HPVs), the E6 and E7 proteins provide the viruses with oncogenic potential. The recent discoveries of PVs without E6 and E7 in different fish species place a new root on the PV tree, and suggest that ancestral PVs consisted of the minimal PV backbone E1-E2-L2-L1 . Bayesian phylogenetic analyses date the most recent common ancestor of the PV backbone to 424 million years ago (Ma). Common ancestry tests on extant E6 and E7 genes indicate that they share a common ancestor dating back to at least 184 Ma. In AlphaPVs infecting Old World monkeys and apes, the appearance of the E5 oncogene 53–58 Ma concurred with (i) a significant increase in substitution rate, (ii) a basal radiation and (iii) key gain of functions in E6 and E7. This series of events was instrumental to construct the extant phenotype of oncogenic HPVs. Our results assemble the current knowledge on PV diversity and present an ancient evolutionary timeline punctuated by evolutionary innovations in the history of this successful viral family. This article is part of the theme issue ‘Silent cancer agents: multi-disciplinary modelling of human DNA oncoviruses’.

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