The BPV1-E2 trans-acting protein can be either an activator or a repressor of the HPV18 regulatory region.

Thierry, Françoise; Yaniv, Moshe

doi:10.1002/j.1460-2075.1987.tb02662.x

Cited by 287 publications

(283 citation statements)

References 28 publications

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“…DNA was prepared by the Qiagen procedure and adjusted to 6 mg per transfection with Blue Scribe plasmid. CAT assays were performed with 1/10 to 1/2 of total cell extract as described earlier (Thierry and Yaniv, 1987).…”

Section: Cell Cultures and Transient Transfectionsmentioning

confidence: 99%

“…This repression is caused by the binding of E2 to the HPV18 early promoter which consequently hinders the binding of two essential transcription factors, TBP and Sp1 (Demeret et al, 1994;Dong et al, 1994;Dostatni et al, 1991;Tan et al, 1992;Thierry and Yaniv, 1987). Repression mainly involves the DNA binding domain of E2, although its transactivation domain may play a role by modulating the stability of the E2/DNA complexes .…”

Section: Introductionmentioning

confidence: 99%

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Papillomavirus E2 induces p53-independent apoptosis in HeLa cells

et al. 1999

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We have previously shown that expression of the papillomavirus E2 protein in HeLa cells induces p53 accumulation and causes both cell cycle arrest and apoptosis. In contrast to growth arrest, onset of apoptosis was not correlated with an increase of p53 transcriptional activity. In the present study, we conducted biochemical and genetic experiments in order to determine whether E2-induced apoptosis was independent of p53 induction. We showed that E2 did not alter the transcription of Bax, a known p53-activated cell death inducer. The time course of apoptotic cell death preceded p53 induction by several hours. Overexpression of the HPV18 E6 oncogene prevented E2-mediated p53 accumulation, but did not alter the rate of cell death. Finally, point mutants of the HPV18 E2 transactivation domain induced apoptosis, although they were unable to induce high p53 accumulation or cell cycle arrest. In addition, the results obtained with these mutants indicated that both transcriptional activation and replication functions of E2 were dispensable for the induction of cell death. These observations show that E2-induced apoptosis is an early event, independent of p53 accumulation and unrelated to downstream p53-dependent transcriptional events.

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Section: Cell Cultures and Transient Transfectionsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Papillomavirus E2 induces p53-independent apoptosis in HeLa cells

et al. 1999

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“…The pattern of the viral DNA integration implies conservation of the viral oncogenes, E6 and E7, which, respectively, induce p53 degradation through the ubiquitin-proteasome pathway (Scheffner et al, 1993) and pRb inactivation (Dyson et al, 1989) and the disruption of the E2 open reading frame encoding a potent repressor of E6/E7 transcription (Thierry and Yaniv, 1987;Bernard et al, 1989;Thierry and Howley, 1991). For high-risk HPV types HPV16 and 18 represent 70-80% of all cervical cancers worldwide (Castellsague et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

The E2F5 repressor is an activator of E6/E7 transcription and of the S-phase entry in HPV18-associated cells

2010

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High-risk papillomavirus type 18 (HPV18) is one of the less represented HPV types in low-grade lesions of the anogenital tract, whereas it occupies the second place in cervical cancer, where it can be found in 16% of the cases worldwide, after HPV16 present in 54% of them. These epidemiological data indicate that HPV18 infection is more prone to carcinogenic progression. The main oncogenic proteins, E6 and E7 of HPV18, are functionally comparable to the homologous proteins of the other highrisk viruses, including HPV16. In this work, we investigated the possibility that the higher oncogenic potential of HPV18 might be due to transcriptional regulation of the E6/E7 oncogenes. By comparing the E6/E7 promoter and enhancer sequences of the mucosal HPV genomes, we identified E2F binding sites specific for HPV18. The E2F family of transcription factors contains activators (E2F1-3) and repressors (E2F4-8) that regulate the transcription of S-phase and mitotic genes and thereby have a crucial role in cell-cycle progression. Surprisingly, we identified E2F5 as a direct activator of HPV18 E6/E7 transcription by sequential silencing of E2F members in HeLa cells. In addition, we could show that E2F5 positively regulates S-phase entry in HeLa cells and that this activation of the cell cycle by a member of the E2F repressor family is specific for HPV18-expressing cells. Diverting the function of E2F5 from a cell-cycle repressor into an activator might contribute to the higher oncogenic potential of HPV18 when compared with other high-risk HPV types.

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“…The concept that loss of E2 repressor function may be critical for malignant progression is supported by experiments showing that re-expression of E2 in cervical cancer cell lines causes growth suppression (Thierry and Yaniv, 1987). Other factors, including sequence variants of HPV subtypes, seem to be important for the oncogenic potential of the virus (Fujinaga et al, 1994;Ellis et al, 1995;Hecht et al, 1995).…”

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confidence: 99%

Gene expression reveals two distinct groups of anal carcinomas with clinical implications

et al. 2008

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Human papillomavirus (HPV) is a major aetiological agent in anal carcinomas. We here present a study of global gene expression using microarray hybridisation in a collection of anal carcinoma biopsies. Quantitative PCR was used to verify expression of selected genes. All biopsies contained integrated DNA of human papillomavirus subtype 16 (HPV16) and expressed HPV16 E7 mRNA. No other subspecies of HPV were detected in these 13 biopsies as assessed by PCR amplification and DNA sequencing. Unsupervised cluster analysis, based on global mRNA expression, divided the tumour biopsies into two distinct groups. Cluster analysis based on a number of high-risk HPV and/or E2F-regulated genes reproduced this biopsy grouping, suggesting that integrated HPV16 substantially influenced global gene expression in approximately half the biopsies studied. The levels of HPV16 E7 mRNA were significantly different between the two groups, but with considerable overlap. Thus, influence on global gene expression could not be absolutely ascribed to the expression level of HPV16. To investigate whether this distinction in gene expression had prognostic impact, we studied protein expression in an independent cohort of 55 anal carcinomas not included in the microarray study of two differentially expressed candidate genes, minichromosome maintenance complex component 7 (MCM7) and cyclin-dependent kinase inhibitor 2A (CDKN2A or p16). HPV status was assessed by in situ hybridisation. There was a significant association between in situ staining for HPV E7 mRNA and immunostaining for CDKN2A (p16) and MCM7 protein. CDKN2A (p16) mRNA was found significantly differentially expressed between the two tumour groups. However, cluster analysis on genes directly regulated by CDKN2A (p16) could not reproduce this split of biopsies into two groups, suggesting that the transcriptional regulatory activity of CDKN2A in these biopsies is inhibited. Furthermore, protein expression of CDKN2A (p16) could not be associated with survival. MCM7 is directly regulated by E2F and induced by HPV, and its mRNA was found differentially expressed between the two tumour groups. High level of MCM7 protein was found to be associated with both improved relapse-free survival (RFS, P ¼ 0.02) and cancer-specific survival (CSS, P ¼ 0.03) in anal cancer patients treated with radiation with or without additional chemotherapy.

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The BPV1-E2 trans-acting protein can be either an activator or a repressor of the HPV18 regulatory region.

Cited by 287 publications

References 28 publications

Papillomavirus E2 induces p53-independent apoptosis in HeLa cells

Papillomavirus E2 induces p53-independent apoptosis in HeLa cells

The E2F5 repressor is an activator of E6/E7 transcription and of the S-phase entry in HPV18-associated cells

Gene expression reveals two distinct groups of anal carcinomas with clinical implications

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