scholarly journals Cancer-Causing Human Papillomavirus E6 Proteins Display Major Differences in the Phospho-Regulation of Their PDZ Interactions

2014 ◽  
Vol 89 (3) ◽  
pp. 1579-1586 ◽  
Author(s):  
Siaw Shi Boon ◽  
Vjekoslav Tomaić ◽  
Miranda Thomas ◽  
Sally Roberts ◽  
Lawrence Banks
Keyword(s):  
Human Papillomavirus ◽  
High Risk ◽  
Signaling Pathways ◽  
Binding Activity ◽  
Binding Potential ◽  
Binding Motif ◽  
Virus Infections ◽  
Hpv E6 ◽  
Hpv Types ◽  
High Risk Hpv

ABSTRACTPrevious studies have shown that the cancer-causing high-risk human papillomavirus (HPV) E6 oncoproteins have PDZ binding potential, an activity which is important for their ability to support the viral life cycle and to cooperate in the induction of malignancy. However, PDZ interactions are not constitutive, and they can be negatively regulated by phosphorylation within the E6 PDZ binding motif (PBM). In this study, we have investigated the differential regulation of the HPV E6 PBMs from diverse high-risk HPV types. We show that, depending on the HPV type, PDZ binding activity can be regulated by phosphorylation with protein kinase A (PKA) or AKT, which, in turn, inhibits PDZ recognition. Such regulation is highly conserved between E6 proteins derived from HPV-16, HPV-18, and HPV-58 while being somewhat weaker or absent from other types such as HPV-31, HPV-33, and HPV-51. In the case of HPV31, PKA phosphorylation occurs within the core of the E6 protein and has no effect on PDZ interactions, and this demonstrates a surprising degree of heterogeneity among the different high-risk HPV E6 oncoproteins in how they are regulated by different cellular signaling pathways.IMPORTANCEThis study demonstrated that the cancer-causing HPV E6 oncoproteins are all subject to posttranslational modification of their extreme C-terminal PDZ binding motifs through phosphorylation. However, the identities of the kinase are not the same for all HPV types. This demonstrates a very important divergence between these HPVs, and it suggests that changes in cell signaling pathways have different consequences for different high-risk virus infections and their associated malignancies.

scholarly journals High-Risk Human Papillomavirus E6 Oncoproteins Interact with 14-3-3ζ in a PDZ Binding Motif-Dependent Manner

2012 ◽  
Vol 87 (3) ◽  
pp. 1586-1595 ◽  
Author(s):  
Siaw Shi Boon ◽  
Lawrence Banks
Keyword(s):  
Cervical Cancer ◽  
Human Papillomavirus ◽  
High Risk ◽  
Pdz Domain ◽  
Binding Motif ◽  
Dependent Manner ◽  
Hpv E6 ◽  
Hpv Types ◽  
High Risk Hpv ◽  
Hpv 18

ABSTRACTCervical cancer develops through the combined activities of the human papillomavirus (HPV) E6 and E7 oncoproteins. A defining characteristic of E6 oncoproteins derived from cancer-causing HPV types is the presence of a PDZ binding motif (PBM) at the extreme carboxy terminus of the protein which is absent from E6 proteins derived from the so-called low-risk HPV types. Within this PBM is also a protein kinase A (PKA) phospho-acceptor site, which is thought to negatively regulate the association of E6 with its PDZ domain-containing substrates. We can now show that phosphorylation of E6 by PKA and/or AKT confers the ability to interact with 14-3-3ζ. The interaction is direct and specific for the high-risk HPV E6 oncoproteins, although there are significant differences in the efficiencies with which HPV-16, HPV-18, and HPV-31 E6 oncoproteins can associate with 14-3-3ζ; this correlates directly with their respective susceptibilities to phosphorylation by PKA and/or AKT. We demonstrate here that the interaction between E6 and 14-3-3ζ also requires integrity of the E6 PBM, and downregulation of 14-3-3ζ results in a marked reduction in the levels of HPV-18 E6 expression in HeLa cells. Using phospho-specific anti-E6 antibodies, we also demonstrate significant levels of E6 phosphorylationin vivo. These studies redefine the potential relevance of the E6 PBM in the development of cervical cancer, suggesting that interaction with 14-3-3ζ, as well as the more well-established interactions with PDZ domain-containing substrates, is likely to be responsible for the biological activities attributed to this region of the high-risk HPV E6 oncoproteins.

scholarly journals Prevalence and Genotyping of Human Papillomavirus (HPV) in Female with High-Risk Behaviour in Dhaka, Bangladesh

1970 ◽  
Vol 25 (1) ◽  
pp. 65-68 ◽  
Author(s):  
Tahmina Sultana ◽  
Mohsina Huq ◽  
Anadil Alam ◽  
Dipak Kumar Mitra ◽  
Donald James Gomes
Keyword(s):  
Cervical Cancer ◽  
Polymerase Chain Reaction ◽  
Human Papillomavirus ◽  
High Risk ◽  
General Population ◽  
Sex Workers ◽  
Chain Reaction ◽  
Hpv Types ◽  
Polymerase Chain ◽  
High Risk Hpv

In developing countries, cervical cancer is the most common cause of cancer related to mortality in women. But the epidemiology of human papillomavirus (HPV) in different areas of Bangladesh is largely unknown both in risk groups and in the general population. The objective of the present study was to determine the risk factors associated with having HPV and the prevalence of high-risk HPV types among women with highrisk behaviour and to assess its potential impact on preventive strategies as the sex workers are at increased risk for sexually transmitted infections (STI), HPV and hence cervical cancer. Cervical swab from 293 sex workers in Dhaka City between August and September 2003 and between February 2005 and May 2006 were screened for HPV DNA using an HPV short fragment (E6) polymerase chain reaction (PCR) based assay. HPV positive samples were genotyped with nested multiplex polymerase chain reaction (NMPCR) for the highrisk types. The overall HPV prevalence in sex workers was 75.8%, whereas for the high risk type it was 49.8%. Prevalence of single genotype and multiple types of HPV was 33.1 and 16.7% respectively. The most prevalent high-risk HPV types, in order of prevalence rate, were HPV16, HPV18, HPV58, HPV45, HPV31 and HPV33. Both HPV 16 and HPV 18 were present in 21% of the cases. Targeting HPV 16 and 18 with prophylactic vaccines could possibly have an important impact on the incidence of invasive cervical carcinoma in this group of women. Primary prevention and cervical cancer screening programmes should be optimized more and run yearly among the general population. It is proposed to screen sex workers when they enter prostitution regardless of their age. Keywords: Human papillomavirus (HPV); High-risk HPV types; Cervical cancer; Sex workersDOI: http://dx.doi.org/10.3329/bjm.v25i1.4861 Bangladesh J Microbiol, Volume 25, Number 1, June 2008, pp 65-68

Prevalence and Distribution of High-Risk Human Papillomavirus Genotypes in Invasive Carcinoma of the Uterine Cervix in Uruguay

2013 ◽  
Vol 23 (3) ◽  
pp. 527-532 ◽  
Author(s):  
Nora Berois ◽  
Patricia De Cremoux ◽  
Daniel Mazal ◽  
Adela Sica ◽  
Mabel Cedeira ◽  
...  
Keyword(s):  
Human Papillomavirus ◽  
High Risk ◽  
Dna Sequences ◽  
Invasive Cervical Cancer ◽  
Human Papillomaviruses ◽  
Geographical Differences ◽  
Hpv Dna ◽  
High Prevalence ◽  
Hpv Types ◽  
High Risk Hpv

ObjectivesPersistent infection with specific genotypes of human papillomaviruses (HPVs) is the main cause of invasive cervical cancer (ICC). Only a few of the various HPV types account for most of the cases worldwide, and geographical differences in their distribution are evident. Data from locally prevalent genotypes are essential in view of introduction of HPV type-specific prophylactic vaccines.MethodsIn this work, we have investigated HPV type distribution in samples of ICC cases that occurred in Uruguayan women. DNA extracted from ICC treated in Centro Hospitalario Pereira Rossell of Montevideo between 1999 and 2007 were analyzed. Search and typing were performed by polymerase chain reaction using generic GP5+/GP6+ primers and specific primers for HPV types 16, 18, 33, and 45. Positive GP5+/GP6+ samples, which were negative for all 4 high-risk HPV-specific types screened were further analyzed by sequencing.ResultsHuman papillomavirus DNA sequences were found in 163 (92.6%) of 176 cases. The most prevalent genotypes were HPV16 (67.6%) and HPV18 (8.5%) followed by HPV45 (6.8%) and HPV33 (3.4%), as single or mixed infection. Other less frequent genotypes were HPV31, HPV35, HPV39, HPV51, HPV52, HPV58, HPV66, and HPV73. The viral type could not be determined (HPV X) in 1 case (0.6%) of the HPV DNA–positive cervical cancers and double infections were found in 1.7% of the cases. The higher percentage of most aggressive HPV (16/18/45) genotypes was detected in cases diagnosed at younger than 60 years old, whereas these genotypes were less frequent in older patients.ConclusionWe conclude that HPV types 16, 18, and 45 have a very high prevalence in ICC of Uruguayan women. Results provide evidence that 16 of 18 infections are more aggressive, but most cancers could be vaccine preventable.

scholarly journals Dynamics of High-Risk Nonvaccine Human Papillomavirus Types after Actual Vaccination Scheme

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Raúl Peralta ◽  
Cruz Vargas-De-León ◽  
Augusto Cabrera ◽  
Pedro Miramontes
Keyword(s):  
Cervical Cancer ◽  
Human Papillomavirus ◽  
High Risk ◽  
Numerical Simulations ◽  
Protective Immunity ◽  
Type Model ◽  
Vaccination Scheme ◽  
Hpv Types ◽  
High Risk Hpv ◽  
The Impact

Human papillomavirus (HPV) has been identified as the main etiological factor in the developing of cervical cancer (CC). This finding has propitiated the development of vaccines that help to prevent the HPVs 16 and 18 infection. Both genotypes are associated with 70% of CC worldwide. In the present study, we aimed to determine the emergence of high-risk nonvaccine HPV after actual vaccination scheme to estimate the impact of the current HPV vaccines. A SIR-type model was used to study the HPV dynamics after vaccination. According to the results, our model indicates that the application of the vaccine reduces infection by target or vaccine genotypes as expected. However, numerical simulations of the model suggest the presence of the phenomenon called vaccine—induced pathogen strain replacement. Here, we report the following replacement mechanism: if the effectiveness of cross-protective immunity is not larger than the effectiveness of the vaccine, then the high-risk nonvaccine genotypes emerge. In this scenario, further studies of infection dispersion by HPV are necessary to ascertain the real impact of the current vaccines, primarily because of the different high-risk HPV types that are found in CC.

scholarly journals Structures of a Human Papillomavirus (HPV) E6 Polypeptide Bound to MAGUK Proteins: Mechanisms of Targeting Tumor Suppressors by a High-Risk HPV Oncoprotein

2007 ◽  
Vol 81 (7) ◽  
pp. 3618-3626 ◽  
Author(s):  
Yi Zhang ◽  
Jhimli Dasgupta ◽  
Runlin Z. Ma ◽  
Lawrence Banks ◽  
Miranda Thomas ◽  
...  
Keyword(s):  
Human Papillomavirus ◽  
High Risk ◽  
Crystal Structures ◽  
Tumor Suppressors ◽  
Specific Binding ◽  
Pdz Domain ◽  
Pdz Domains ◽  
Hpv E6 ◽  
C Terminus ◽  
High Risk Hpv

ABSTRACT Human papillomavirus (HPV) E6 oncoprotein targets certain tumor suppressors such as MAGI-1 and SAP97/hDlg for degradation. A short peptide at the C terminus of E6 interacts specifically with the PDZ domains of these tumor suppressors, which is a property unique to high-risk HPVs that are associated with cervical cancer. The detailed recognition mechanisms between HPV E6 and PDZ proteins are unclear. To understand the specific binding of cellular PDZ substrates by HPV E6, we have solved the crystal structures of the complexes containing a peptide from HPV18 E6 bound to three PDZ domains from MAGI-1 and SAP97/Dlg. The complex crystal structures reveal novel features of PDZ peptide recognition that explain why high-risk HPV E6 can specifically target these cellular tumor suppressors for destruction. Moreover, a new peptide-binding loop on these PDZs is identified as interacting with the E6 peptide. Furthermore, we have identified an arginine residue, unique to high-risk HPV E6 but outside the canonical core PDZ recognition motif, that plays an important role in the binding of the PDZs of both MAGI-I and SAP97/Dlg, the mutation of which abolishes E6's ability to degrade the two proteins. Finally, we have identified a dimer form of MAGI-1 PDZ domain 1 in the cocrystal structure with E6 peptide, which may have functional relevance for MAGI-1 activity. In addition to its novel insights into the biochemistry of PDZ interactions, this study is important for understanding HPV-induced oncogenesis; this could provide a basis for developing antiviral and anticancer compounds.

scholarly journals Additional Human Papillomavirus Types Detected by the Hybrid Capture Tube Test among Samples from Women with Cytological and Colposcopical Atypia

2000 ◽  
Vol 38 (1) ◽  
pp. 408-411
Author(s):  
József Kónya ◽  
György Veress ◽  
Attila Juhász ◽  
Krisztina Szarka ◽  
Tamás Sápy ◽  
...  
Keyword(s):  
Human Papillomavirus ◽  
High Risk ◽  
Fragment Length Polymorphism ◽  
Low Risk ◽  
Double Positive ◽  
Detection Range ◽  
Hybrid Capture ◽  
Pcr Rflp ◽  
Hpv Types ◽  
High Risk Hpv

ABSTRACT The type specificity of the human papillomavirus (HPV) Hybrid Capture Tube (HCT) test was evaluated by using typing with PCR (MY09-MY11)-restriction fragment length polymorphism (RFLP) and sequencing. All samples HCT test positive for only low-risk HPV ( n = 15) or only high-risk HPV ( n = 102) were confirmed, whereas 9 of 12 HCT test double-positive samples contained only high-risk HPV types as determined by PCR-RFLP. Several high-risk HPV types (HPV-53, -58, -62, -66, -CP8304, and -MM4) not included in the HCT test were indeed detected, indicating a broader detection range with retained distinction between low-risk and high-risk HPV types.

scholarly journals Human Papillomavirus Type Distribution and Correlation with Cyto-Histological Patterns in Women from the South of Italy

2009 ◽  
Vol 2009 ◽  
pp. 1-4 ◽  
Author(s):  
Paola Menegazzi ◽  
Luisa Barzon ◽  
Giorgio Palù ◽  
Elisa Reho ◽  
Luigi Tagliaferro
Keyword(s):  
Human Papillomavirus ◽  
High Risk ◽  
Hpv Infection ◽  
Multiple Infection ◽  
Multiple Infections ◽  
The South ◽  
Hpv 16 ◽  
Specific Distribution ◽  
Hpv Types ◽  
High Risk Hpv

Human papillomavirus (HPV) type-specific distribution was evaluated in genital samples collected from 654 women from the South of Italy undergoing voluntary screening and correlated with cyto-histological abnormalities. HPV DNA was detected in 45.9% of the samples, 41.7% of which had multiple infection and 89.0% had high-risk HPV infection. The prevalence of HPV infection and the rate of multiple infections decreased with age, suggesting natural selection of HPV types with better fitness. In line with other Italian studies, the most common HPV types were HPV-6 and HPV-16, followed by HPV-51, HPV-31, HPV-53, and HPV-66, in women with both normal and abnormal cytology. Cervical intraepithelial lesions grade 2 or 3 were associated with high-risk HPV-16, HPV-18, HPV-31, and HPV-51 infection. These data indicate that prophylactic HPV vaccination is expected to reduce the burden of HPV-related cervical lesions in this population, but also suggest the potential utility of new vaccines with larger type coverage.

scholarly journals Cellular Changes Induced by Low-Risk Human Papillomavirus Type 11 in Keratinocytes That Stably Maintain Viral Episomes

2001 ◽  
Vol 75 (16) ◽  
pp. 7564-7571 ◽  
Author(s):  
Jennifer T. Thomas ◽  
Stephen T. Oh ◽  
Scott S. Terhune ◽  
Laimonis A. Laimins
Keyword(s):  
Human Papillomavirus ◽  
Life Cycle ◽  
High Risk ◽  
Life Cycles ◽  
Low Risk ◽  
Global Changes ◽  
Culture Methods ◽  
Transfected Cells ◽  
Hpv Types ◽  
High Risk Hpv

ABSTRACT Infections by low-risk papillomavirus types, such as human papillomavirus (HPV) type 6 (HPV-6) and HPV-11, induce benign genital warts that rarely progress to malignancy. In contrast, lesions induced by high-risk HPV types have the potential to progress to cancer. Considerable information is available concerning the pathogenesis of high-risk HPV types, but little is known about the life cycle of low-risk HPV types. Although functionally distinct, both high- and low-risk virus types infect keratinocytes and induce virion production upon differentiation. This information suggests that they may share common mechanisms for regulating their productive life cycles. Using tissue culture methods developed to study high-risk HPV types, we examined the ability of HPV-11 to be stably maintained as episomes following transfection of normal human keratinocytes with cloned viral DNA. HPV-11 genomes were found to be maintained in keratinocytes for extended passages in cultures in 14 independent experiments involving transfection of cloned HPV-11 DNA. Interestingly, the HPV-11-positive cells exhibited an extended life span that averaged approximately twofold longer than that of control neomycin-transfected cells. In organotypic cultures, HPV-11-positive cells exhibited altered differentiation patterns, but the extent of disruption was less severe than that seen with high-risk HPV types. In addition, the amplification of HPV-11 DNA, as well as the induction of several viral messages, was observed following differentiation of transfected cells in semisolid media. To determine whether global changes in cellular gene expression induced by HPV-11 were similar to those observed with high-risk HPV-31 (Y. E. Chang and L. A. Laimins, J. Virol. 74:4174–4182, 2000), microarray analysis of 7,075 expressed sequences was performed. A spectrum of cellular genes different from that previously reported for HPV-31 was found to be activated or repressed by HPV-11. The expression of only a small set of genes was similarly altered by both high- and low-risk HPV types. This result suggests that different classes of HPVs have distinct effects on global cellular transcription patterns during infection. The methods described allow for a genetic analysis of HPV-11 in the context of its differentiation-dependent life cycle.

scholarly journals Vaccine-Relevant Human Papillomavirus (HPV) Infections and Future Acquisition of High-Risk HPV Types in Men

2012 ◽  
Vol 206 (5) ◽  
pp. 669-677 ◽  
Author(s):  
Anne F. Rositch ◽  
Michael G. Hudgens ◽  
Danielle M. Backes ◽  
Stephen Moses ◽  
Kawango Agot ◽  
...  
Keyword(s):  
Human Papillomavirus ◽  
High Risk ◽  
Hpv Types ◽  
High Risk Hpv

Human papillomavirus prevalence to age 60 years among Australian women prevaccination

Sexual Health ◽  
2015 ◽  
Vol 12 (4) ◽  
pp. 353 ◽  
Author(s):  
Julia M. L. Brotherton ◽  
John R. Condon ◽  
Peter B. McIntyre ◽  
Sepehr N. Tabrizi ◽  
Michael Malloy ◽  
...  
Keyword(s):  
Human Papillomavirus ◽  
High Risk ◽  
Sexual Debut ◽  
Cervical Screening ◽  
Hpv Vaccination ◽  
Normal Cytology ◽  
Screening Programs ◽  
Hpv Types ◽  
High Risk Hpv ◽  
Second Peak

Background The prevalence of human papillomavirus (HPV) at the cervix varies with age, peaking following sexual debut and declining thereafter in most populations. In some populations, a second peak is observed. Here we describe the prevalence of HPV at the cervix among Australian women before the commencement of the HPV vaccination program. Methods: Women aged 15 to 60 years attending health services for cervical screening between 2005 and 2008 were invited to participate. Liquid based cervical specimens were tested for 37 types of HPV using linear array. The percentage and 95% confidence interval of women with any type of HPV, any of 13 high risk HPV types, and with vaccine-preventable HPV types (types 6, 11, 16 and 18) were estimated in 5-year age bands. Results: Among 1929 women aged 15–60 years, HPV prevalence peaked at 64% at age 15–20 years, then declined gradually to 12% at age 41–45 years, whereafter it rose to 19% in women 51–55 years then returned to 14% in 56–60 year olds. Prevalence curves were similar for high-risk HPV types and vaccine-targeted HPV types 6, 11, 16 and 18 and when results were restricted to women with only normal cytology. Conclusions: The shape of the prevalence curve we observed is similar to those from other Western populations. Variation in prevalence curves is likely due to differences in sexual behaviour between populations and over time, reactivation of HPV during perimenopause, and possibly the presence of cervical screening programs. These data are the first such data from the Oceania region.

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