Degradation of p53 by Human Alphapapillomavirus E6 Proteins Shows a Stronger Correlation with Phylogeny than Oncogenicity

Fu, Leiping; Doorslaer, Koenraad Van; Chen, Zigui; Ristriani, Tutik; Masson, Murielle; Travé, Gilles; Burk, Robert D.

doi:10.1371/journal.pone.0012816

Cited by 64 publications

(63 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Growth characteristics were not related to the relatively small differences seen in transgene DNA copy numbers and expression levels. Overall, our Western blot results are in line with earlier reports showing p53 and pRb degradation by (probable) hrHPV types, but not by HPV11 (11)(12)(13)45). Similar to other in vitro studies (11,12), the p53 degradation capacities varied among the hrHPV types.…”

Section: Discussionsupporting

confidence: 92%

“…Furthermore, a large, randomized, controlled prospective trial conducted in the Netherlands has revealed that among hrHPV-positive women with normal cytology or borderline to moderate dyskaryosis, those infected with hrHPV types 16, 18, 31, and 33 have an increased 18-month risk of CIN3 or cancer (8). Apart from type-specific differences in viral persistence (9), these and other data also point to the existence of different oncogenic properties of the various high-risk types.Although some non-HPV16 and -18 types recently received some attention (11)(12)(13)(14), functional studies on transforming properties of hrHPV are mainly limited to HPV16 and HPV18. We and others have previously demonstrated that HPV16 and HPV18 can induce immortalization of primary human foreskin keratinocytes (HFKs) by successive bypass of two proliferative life span barriers, i.e., senescence and crisis (reviewed in reference 15).…”

mentioning

confidence: 99%

“…Although some non-HPV16 and -18 types recently received some attention (11)(12)(13)(14), functional studies on transforming properties of hrHPV are mainly limited to HPV16 and HPV18. We and others have previously demonstrated that HPV16 and HPV18 can induce immortalization of primary human foreskin keratinocytes (HFKs) by successive bypass of two proliferative life span barriers, i.e., senescence and crisis (reviewed in reference 15).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Differential In Vitro Immortalization Capacity of Eleven, Probable High-Risk Human Papillomavirus Types

Schütze

Snijders

Bosch

et al. 2014

J Virol

View full text Add to dashboard Cite

bEpidemiological studies identified 12 high-risk HPV (hrHPV) types and 8 probable/possible hrHPV types that display different cancer risks. Functional studies on transforming properties of hrHPV are mainly limited to HPV16 and -18, which induce immortalization of human foreskin keratinocytes (HFKs) by successive bypass of two proliferative life span barriers, senescence and crisis. Here, we systematically compared the in vitro immortalization capacities, as well as influences on p53, pRb, hTERT, growth behavior, and differentiation capacity, of nine hrHPV types (HPV16, -18, -31, -33, -35, -45, -51, -52, and -59), and two probable hrHPV types (HPV66 and -70). By retroviral transduction, the respective E6/E7 coding sequences were expressed in HFKs from two or three independent donors. Reduced p53 levels and low-level hTERT expression in early-passage cells, as seen in HPV16-, -31-, -33-, and -35-, and to a lesser extent HPV18-transduced HFKs, was associated with continuous growth and an increased immortalization capacity. Less frequent immortalization by HPV45 and -51 and immortalization by HPV66 and -70 was preceded by an intervening period of strongly reduced growth (crisis) without prior increase in hTERT expression. Immortalization by HPV59 was also preceded by a period crisis, despite the onset of low hTERT expression at early passage. HPV52 triggered an extended life span but failed to induce immortality. Variations in p53 and pRb levels were not correlated with differences in alternative E6/E7 mRNA splicing in all hrHPV-transduced HFKs. On collagen rafts, transductants showed disturbed differentiation reminiscent of precancerous lesions. In conclusion, in vitro oncogenic capacities differ between the established hrHPV types, and both some established and probable hrHPV types display weak or moderate immortalization potential. C ervical cancer, the third most common cancer among women worldwide, is caused by a persistent infection with certain types of human papillomavirus (HPV) (1, 2). Most HPV infections are transient and are cleared within 1 to 2 years. However, a fraction of infections eventually give rise to either squamous cell carcinoma (SCC) or adenocarcinoma (AdCA) of the cervix. SCCs develop from so-called cervical intraepithelial neoplasia (CIN) precursor lesions. Low-grade CIN lesions (CIN1) mostly reflect a productive infection in which viral replication and virion production are linked to the differentiation program of the epithelium. High-grade CIN lesions (CIN2/3) mainly represent transforming infections and are characterized by deregulated expression of the early viral E6 and E7 genes in the proliferating basal cells of the epithelium (3, 4).HPV types belonging to the alpha (␣) genus can infect the cervical mucosa (5) and are classified into low-risk (lrHPV) and high-risk (hrHPV) HPV based on their association with malignancy (6). Infections with lrHPV types, e.g., HPV type 6 (HPV6) and HPV11, are associated with benign warts or low-grade lesions, whereas infections with hrHPV can give rise ...

show abstract

Section: Discussionsupporting

confidence: 92%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Differential In Vitro Immortalization Capacity of Eleven, Probable High-Risk Human Papillomavirus Types

Schütze

Snijders

Bosch

et al. 2014

J Virol

View full text Add to dashboard Cite

show abstract

“…The genome segment contained from the LCR to the E6 and E7 genes encodes oncoproteins described as essential for HPV-induced carcinogenesis in vivo 3 . E6 and E7 interact with tumor suppressor proteins p53 4 and pRB 5 , respectively, resulting in alteration of the DNA repair process and cell-cycle control.…”

Section: Introductionmentioning

confidence: 99%

Prevalence of Human Papillomavirus in Women from the State of Michoacan, Mexico, Showed High Frequency of Unusual Virus Genotypes

Jácome-Galarza¹,

Ito-Nakashimada

Figueroa-Aguilar

et al. 2017

RIC

View full text Add to dashboard Cite

Background: Human papillomaviruses (HPVs), the leading cause of cervical cancer, are distributed worldwide, with high prevalence in developing countries. Objective: The objective of the study is to know the prevalence and genotypes of HPV in women from the state of Michoacán and the Women's Hospital in Morelia, Michoacán. Materials and Methods: Cervical smear samples (159,288) were subjected to HPV detection by hybrid capture 2. A subsample of 484 patients from the Women's Hospital was studied by Papanicolaou test and linear array HPV genotyping, and when positive, patients were also examined by colposcopy and histopathology. Results: The overall prevalence for HPV in Michoacán State was 7.74%; 7.11% in 2009, 6.46% in 2010, 9.58% in 2011, and 8.43% in 2012. The highest prevalence was found in the age groups < 25 and 25-34 years. The prevalence at the Women's Hospital was 8.51%. Cytological examination revealed normal cytology in 64.44% of samples, 26.66 % with low-grade and 8.88 % with high-grade squamous intraepithelial lesion (HSIL). However, by colposcopy, normal tissue appearance was found only in 26.66%; 51% were reclassified as low-grade squamous intraepithelial lesion, 17.77% as HSIL, and in 4.4% atrophy was observed. The most prevalent genotype in single infections was HPV59, followed by HPV51 and HPV45. Double infections occurred with the following genotypes:

show abstract

“…Only recently have large-scale studies begun to investigate the p53 degradation activities of several E6 types (20,26). These studies provided important information as to which E6 types can promote the degradation of p53 in vitro, using in vitro-translated proteins (26), and in vivo, in transfected cells (20).…”

mentioning

confidence: 99%

p53 Degradation Activity, Expression, and Subcellular Localization of E6 Proteins from 29 Human Papillomavirus Genotypes

Mésplède

Gagnon

Bergeron-Labrecque

et al. 2012

J Virol

View full text Add to dashboard Cite

Human papillomaviruses (HPVs) are the etiological agents of cervical cancer and other human malignancies. HPVs are classified into high-and low-risk genotypes according to their association with cancer. Host cell transformation by high-risk HPVs relies in part on the ability of the viral E6 protein to induce the degradation of p53. We report the development of a cellular assay that accurately quantifies the p53 degradation activity of E6 in vivo, based on the fusion of p53 to Renilla luciferase (RLuc-p53). This assay was used to measure the p53 degradation activities of E6 proteins from 29 prevalent HPV types and variants of HPV type 16 (HPV16) and HPV33 by determining the amount of E6 expression vector required to reduce by half the levels of RLuc-p53 (50% effective concentration [EC 50 ]). These studies revealed an unexpected variability in the p53 degradation activities of different E6 proteins, even among active types whose EC 50 s span more than 2 log units. Differences in activity were greater between types than between variants and did not correlate with differences in the intracellular localization of E6, with most being predominantly nuclear. Protein and mRNA expression of the 29 E6 proteins was also examined. For 16 high-risk types, spliced transcripts that encode shorter E6*I proteins of variable sizes and abundances were detected. Mutation of the splice donor site in five different E6 proteins increased their p53 degradation activity, suggesting that mRNA splicing can limit the activity of some highrisk E6 types. The quantification of p53 degradation in vivo represents a novel tool to systematically compare the oncogenic potentials of E6 proteins from different HPV types and variants.

show abstract

Degradation of p53 by Human Alphapapillomavirus E6 Proteins Shows a Stronger Correlation with Phylogeny than Oncogenicity

Cited by 64 publications

References 33 publications

Differential In Vitro Immortalization Capacity of Eleven, Probable High-Risk Human Papillomavirus Types

Differential In Vitro Immortalization Capacity of Eleven, Probable High-Risk Human Papillomavirus Types

Prevalence of Human Papillomavirus in Women from the State of Michoacan, Mexico, Showed High Frequency of Unusual Virus Genotypes

p53 Degradation Activity, Expression, and Subcellular Localization of E6 Proteins from 29 Human Papillomavirus Genotypes

Contact Info

Product

Resources

About