A naturally occurring variant of HPV-16 E7 exerts increased transforming activity through acquisition of an additional phospho-acceptor site

Abidine, Amira Zine El; Tomaić, Vjekoslav; Rhouma, Rahima Bel Haj; Massimi, Paola; Guizani, Ikram; Boubaker, Samir; Ennaifer, Emna; Banks, Lawrence

doi:10.1016/j.virol.2016.10.023

Cited by 28 publications

(22 citation statements)

References 35 publications

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“…Previous studies have shown that the CKII phospho-acceptor site in HPV-16 E7 plays an important role in the HPV life cycle, and in the ability of E7 to bring about cell transformation in a variety of different experimental settings [15, 27]. Furthermore, recent studies showed that a variant HPV-16 E7, in which an extra CKII phospho-site was present at N29S, exhibited a marked increase in transforming potential [20]. Many of these activities have been linked to the effects of phosphorylation on the ability of E7 to interact with some of its cellular substrates.…”

Section: Discussionmentioning

confidence: 99%

“…At a molecular level this phosphorylation event is also thought to increase the interaction of E7 with a number of cellular target proteins, including pRb and TBP [16–19]. Indeed, recent studies identified a variant HPV-16 E7 with an extra CKII phospho-acceptor site, and this appeared to correlate with increased transforming potential [20]. Finally, recent structural studies have also begun to shed light on how phosphorylation of E7 might affect its overall structure, and thereby also affect target recognition [21].…”

Section: Introductionmentioning

confidence: 99%

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The HPV-18 E7 CKII phospho acceptor site is required for maintaining the transformed phenotype of cervical tumour-derived cells

et al. 2019

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The Human Papillomavirus E7 oncoprotein plays an essential role in the development and maintenance of malignancy, which it achieves through targeting a number of critical cell control pathways. An important element in the ability of E7 to contribute towards cell transformation is the presence of a Casein Kinase II phospho-acceptor site within the CR2 domain of the protein. Phosphorylation is believed to enhance E7 interaction with a number of different cellular target proteins, and thereby increase the ability of E7 to enhance cell proliferation and induce malignancy. However, there is little information on how important this site in E7 is, once the tumour cells have become fully transformed. In this study, we have performed genome editing of the HPV-18 E7 CKII recognition site in C4-1 cervical tumour-derived cells. We first show that mutation of HPV18 E7 S32/S34 to A32/A34 abolishes CKII phosphorylation of E7, and subsequently we have isolated C4-1 clones containing these mutations in E7. The cells continue to proliferate, but are somewhat more slow-growing than wild type cells, reach lower saturation densities, and are also more susceptible to low nutrient conditions. These cells are severely defective in matrigel invasion assays, partly due to downregulation of matrix metalloproteases (MMPs). Mechanistically, we find that phosphorylation of E7 plays a direct role in the ability of E7 to activate AKT signaling, which in turn is required for optimal levels of MMP secretion. These results demonstrate that the E7 CKII phospho-acceptor site thus continues to play an important role for E7’s activity in cells derived from cervical cancers, and suggests that blocking this activity of E7 could be expected to have therapeutic potential.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The HPV-18 E7 CKII phospho acceptor site is required for maintaining the transformed phenotype of cervical tumour-derived cells

et al. 2019

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“…For example, CKII phosphorylation of E7 increases the binding affinity of HPV16 E7 for the TATA box-binding protein (TBP) (245), and it is required for efficient transformation by E7 (246). Interestingly, an additional phosphorylation site at serine position 29 exists in a natural E7 variant (N29S) and leads to increased levels of phosphorylation by CKII, which increases the interaction of E7 with TBP and pRb, and its transforming activity in primary rodent cells (247).…”

Section: Transforming Activities Of Pvsmentioning

confidence: 99%

Mucosal and Cutaneous Human Papillomavirus Infections and Cancer Biology

2019

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Papillomaviridae is a family of small non-enveloped icosahedral viruses with double-stranded circular DNA. More than 200 different human papillomaviruses (HPVs) have been listed so far. Based on epidemiological data, a subgroup of alphapapillomaviruses (alpha HPVs) was referred to as high-risk (HR) HPV types. HR HPVs are the etiological agents of anogenital cancer and a subset of head and neck cancers. The cutaneous HPV types, mainly from beta and gamma genera, are widely present on the surface of the skin in the general population. However, there is growing evidence of an etiological role of betapapillomaviruses (beta HPVs) in non-melanoma skin cancer (NMSC), together with ultraviolet (UV) radiation. Studies performed on mucosal HR HPV types, such as 16 and 18, showed that both oncoproteins E6 and E7 play a key role in cervical cancer by altering pathways involved in the host immune response to establish a persistent infection and by promoting cellular transformation. Continuous expression of E6 and E7 of mucosal HR HPV types is essential to initiate and to maintain the cellular transformation process, whereas expression of E6 and E7 of cutaneous HPV types is not required for the maintenance of the skin cancer phenotype. Beta HPV types appear to play a role in the initiation of skin carcinogenesis, by exacerbating the accumulation of UV radiation-induced DNA breaks and somatic mutations (the hit-and-run mechanism), and they would therefore act as facilitators rather than direct actors in NMSC. In this review, the natural history of HPV infection and the transforming properties of various HPV genera will be described, with a particular focus on describing the state of knowledge about the role of cutaneous HPV types in NMSC.

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“…There were numerous studies of HPV about cervical lesions, which focused on the relationship between cervical lesions and HPV-related gene and protein, such as L1 protein, L2 protein, E6, and E7 gene. [4–7] The L1 protein as the main capsid protein of HPV played an important role to recognize the host cell and keep persistent infection, which was a good index to evaluate the infection state in host cell. [8] Previous studies showed that the quantity of L1 protein was declining with aggravate of cervical cell lesion, L1 gene was the coding gene of L1 protein, its methylation was the major reason of L1 protein decreasing, which showed positive correlation to the degree of cervical lesions.…”

Section: Introductionmentioning

confidence: 99%

Increased HPV L1 gene methylation and multiple infection status lead to the difference of cervical epithelial cell lesion in different ethnic women of Xinjiang, China

et al. 2017

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Human papillomavirus (HPV) L1 gene methylation deeply involved in the progression and heterogeneity of cervical cell epithelial lesions. The DNA ploidy also represented the early lesions of cervical cell, and it was associated with different HPV infection status in different ethnic women. So, the research was to explore whether it was possible that HPV L1 gene methylation and HPV infection status as the risk factors to lead to the differences of cervical epithelial cells’ lesions in different ethnics women.The flow-through hybridization and gene chip for HPV genotypes test, general characteristics, and cervical exfoliated cell samples were collected from 94 Uygur and 79 Han women with HPV-16 infection. The cases were divided into the single HPV-16 (sHPV-16) infection group and multiple HPV-16 (mHPV-16) infection group in each ethnic women. The DNA ploidy was analyzed by flow cytometry, and the methylation-sensitive high resolution melting (MS-HRM) was used to test the HPV-16 L1 gene methylation, the results of methylation was segmented into mild methylation, moderate methylation, and severe methylation groups. Multifactor logistic analysis explored the relation between DNA heteroploid and HPV-16 infection status, HPV-16 L1 gene methylation in different ethnic women.The higher proportion of mHPV-16 infection in Uygur than Han women (61.7% vs 38.0%). L1 gene methylation had statistic difference between single and mHPV-16 infection under the same ethnic women. The proportion of DNA heteroploid had statistic difference between different HPV-16 infection status or different L1 gene methylation grades in Han or Uygur women. Both L1 gene methylation and HPV infection status were the risk factors of DNA heteroploid. Compared to the sHPV-16 infection, the odds ratio (OR) of mHPV-16 infection were 4.409 (CI: 1.398–13.910) and 3.279 (CI: 1.069–10.060) in Han and Uygur women. Compared the mild L1 gene methylation, the OR of moderate L1 gene methylation were 3.313 (CI: 1.002–10.952) and 5.075 (CI: 1.385–18.603) in Han and Uygur women, the OR of severe L1 gene methylation were 20.592 (CI: 3.691–114.880) and 63.634 (CI: 10.400–389.368) in Han and Uygur women.The study first reported that HPV L1 gene methylation and HPV infection status were the risk factors to the DNA heteroploid of cervical cell in different ethnics women, HPV L1 gene methylation and infection status should be recommended to the existing system of cervical lesion screening in order to provide better serves for the HPV infected women, especially for the ethnic women with high proportion of severe L1 gene methylation and multiple infection status.

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A naturally occurring variant of HPV-16 E7 exerts increased transforming activity through acquisition of an additional phospho-acceptor site

Cited by 28 publications

References 35 publications

The HPV-18 E7 CKII phospho acceptor site is required for maintaining the transformed phenotype of cervical tumour-derived cells

The HPV-18 E7 CKII phospho acceptor site is required for maintaining the transformed phenotype of cervical tumour-derived cells

Mucosal and Cutaneous Human Papillomavirus Infections and Cancer Biology

Increased HPV L1 gene methylation and multiple infection status lead to the difference of cervical epithelial cell lesion in different ethnic women of Xinjiang, China

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