The E6 and E7 genes of the human papillomavirus type 16 together are necessary and sufficient for transformation of primary human keratinocytes

Münger, Karl; Phelps, William C.; Bubb, Vivien J.; Howley, Peter; Schlegel, Richard

doi:10.1128/jvi.63.10.4417-4421.1989

Cited by 1,177 publications

(404 citation statements)

References 40 publications

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“…Since the description of active viral E6/E7 genes in cervical cancer cells (6) and their identification as major HPV oncogenes (10), experimental evidence derived from many studies suggested that expression of the E6 and E7 oncogenes is necessary for the induction and maintenance of the transformed phenotype (2,42). HPV-16 E6-E7 anti-sense RNA inhibits tumorigenicity of cervical cancer cells in nude mice (43), and siRNA targeting of the viral E6/E7 mRNA efficiently kills human papillomavirus-positive cancer cells (44).…”

Section: Discussionmentioning

confidence: 99%

High level HPV‐16 E7 oncoprotein expression correlates with reduced pRb‐levels in cervical biopsies

et al. 2004

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High-risk human papillomaviruses (HPVs) are major etiological agents of cervical cancer. Despite excellent epidemiological evidence for a direct role of HPV-16 in cervical carcinogenesis, molecular pathways underlying carcinogenesis in vivo remain obscure. The E7 gene is required for immortalization and maintenance of the transformed phenotype in vitro; however, little is known about its role for tumorigenesis in vivo. The E7 gene codes for an unstable protein the abundance of which in cervical biopsies is unknown. We show here that E7 protein levels strongly increase during cervical carcinogenesis, underlining its fundamental role in cervical cancer. The E7 protein was found predominantly in the nucleus and to a minor extent in the cytoplasm in the cervical cancer cell line Ca Ski in vitro and in invasive cervical carcinoma in situ, suggesting that nuclear resident E7 plays a major role in cervical carcinogenesis in humans. The retinoblastoma protein (pRb) is a major E7-target in vitro. We show here that pRb expression is initially upregulated in LSIL and disappears in later stages concomitant with increased E7 levels, suggesting that E7-driven degradation of pRb is involved in cervical tumorigenesis in humans.

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Section: Discussionmentioning

confidence: 99%

High level HPV‐16 E7 oncoprotein expression correlates with reduced pRb‐levels in cervical biopsies

et al. 2004

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“…1 Chronic infection of the genital tract by the human papillomavirus (HPV) is the cause of cervical cancer, 2 and the expression of the oncogenic E6 and E7 proteins from HPV is required for the onset and maintenance of malignant transformation. 3 We developed a therapeutic vaccine against cervical cancer based on adenylate cyclase from Bordetella pertussis that carries the HPV E7 oncoprotein (CyaA-E7). This vaccine is able to eradicate palpable tumors generated by the subcutaneous graft of E6/E7-expressing TC-1 cells in a mouse model of cervical cancer.…”

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confidence: 99%

B cells promote tumor progression in a mouse model of HPV‐mediated cervical cancer

Tang

Dadaglio

Oberkampf

et al. 2016

Intl Journal of Cancer

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Enhancing anti-tumor immunity and preventing tumor escape are efficient strategies to increase the efficacy of therapeutic cancer vaccines. However, the treatment of advanced tumors remains difficult, mainly due to the immunosuppressive tumor microenvironment. Regulatory T cells and myeloid-derived suppressor cells have been extensively studied, and their role in suppressing tumor immunity is now well established. In contrast, the role of B lymphocytes in tumor immunity remains unclear because B cells can promote tumor immunity or display regulatory functions to control excessive inflammation, mainly through IL-10 secretion. Here, in a mouse model of HPV-related cancer, we demonstrate that B cells accumulated in the draining lymph node of tumor-bearing mice, due to a prolonged survival, and showed a decreased expression of MHC class II and CD86 molecules and an increased expression of Ly6A/E, PD-L1 and CD39, suggesting potential immunoregulatory properties. However, B cells from tumor-bearing mice did not show an increased ability to secrete IL-10 and a deficiency in IL-10 production did not impair tumor growth. In contrast, in B cell-deficient μMT mice, tumor rejection occurred due to a strong T cell-dependent anti-tumor response. Genetic analysis based on single nucleotide polymorphisms identified genetic variants associated with tumor rejection in μMT mice, which could potentially affect reactive oxygen species production and NK cell activity. Our results demonstrate that B cells play a detrimental role in anti-tumor immunity and suggest that targeting B cells could enhance the anti-tumor response and improve the efficacy of therapeutic cancer vaccines.

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“…The products of the viral oncogenes E6 and E7 from high-risk viruses have been implicated in carcinogenesis because their expression is sufficient for the immortalization of primary human keratinocytes in vitro. [2][3][4] E6 targets p53 for ubiquitin-mediated degradation, while E7 binds and inactivates the product of the tumor-suppressor gene Rb. 5,6 Despite this efficient program for inactivating tumor-suppressor proteins, development of cervical carcinoma is a multistep process for which E6 and E7 are necessary but not sufficient.…”

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confidence: 99%

Selective suppression of monocyte chemoattractant protein‐1 expression by human papillomavirus E6 and E7 oncoproteins in human cervical epithelial and epidermal cells

Kleine-Lowinski

Rheinwald

Fichorova

et al. 2003

Intl Journal of Cancer

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Infection of cervical keratinocytes by high-risk HPV is in-HPVs are etiologically involved in carcinoma of the uterine cervix. Among the nearly 90 HPV serotypes isolated to date, a subset of high-risk viruses has been found in over 90% of human cervical cancers. 1 These include HPV16 (detected in 50% of tumors), HPV18, HPV31 and HPV33. The products of the viral oncogenes E6 and E7 from high-risk viruses have been implicated in carcinogenesis because their expression is sufficient for the immortalization of primary human keratinocytes in vitro. 2-4 E6 targets p53 for ubiquitin-mediated degradation, while E7 binds and inactivates the product of the tumor-suppressor gene Rb. 5,6 Despite this efficient program for inactivating tumor-suppressor proteins, development of cervical carcinoma is a multistep process for which E6 and E7 are necessary but not sufficient. Other genetic changes are required, which may be a consequence, in part, of the chromosomal instability produced by expression of these oncogenes. 7 In addition, however, the host can mount an immune response against HPV, which keeps the infection in a clinically latent state, and this latency must be overcome for cervical cancer to appear. 1,8 -10 Very little is known about the regulation of the immune response directed against HPV-infected epithelial cells. Although epithelial cells can present antigen and release proinflammatory cytokines when activated, [11][12][13][14] there is little or no inflammation at the site of primary HPV infection, 8 and the few inflammatory cells that are present appear not to be activated. 15 In addition, as epithelial dysplasia worsens during progression toward cervical carcinoma, the cervical mucosa is gradually depleted of macrophages, T cells and Langerhans cells. 16 These observations suggest that HPV is capable of suppressing the host's immune and inflammatory responses to viral infection and transformation.One of the earliest cellular responses to injury or infection is the release of chemokines, which are low m.w. chemoattractant proteins that elicit local infiltration of inflammatory and immune cells. 17 The chemokine MCP-1 is particularly relevant in the setting of viral infection because of its ability to attract monocytes, memory T cells and NK cells in vivo. 18 However, even though MCP-1 expression is induced after infection by a variety of RNA and DNA viruses, MCP-1 expression is suppressed after epithelial cell infection by HPV in vitro. 19 This parallels the situation in vivo, where advancing cervical intraepithelial neoplasia is associated with loss of MCP-1 expression. 20 The mechanisms responsible for HPV-mediated suppression of MCP-1 expression are unclear. The present study was undertaken to examine the effects of HPV E6 and E7 on chemokine expression by primary epithelial cells of the reproductive tract. Surprisingly, we found that viral oncogenes selectively render MCP-1 unresponsive to induction by proinflammatory cytokines and that this refractoriness is also seen in most cervical carcinoma cell li...

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The E6 and E7 genes of the human papillomavirus type 16 together are necessary and sufficient for transformation of primary human keratinocytes

Cited by 1,177 publications

References 40 publications

High level HPV‐16 E7 oncoprotein expression correlates with reduced pRb‐levels in cervical biopsies

High level HPV‐16 E7 oncoprotein expression correlates with reduced pRb‐levels in cervical biopsies

B cells promote tumor progression in a mouse model of HPV‐mediated cervical cancer

Selective suppression of monocyte chemoattractant protein‐1 expression by human papillomavirus E6 and E7 oncoproteins in human cervical epithelial and epidermal cells

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