HPV-16 E7 but not E6 oncogenic protein triggers both cellular immunosuppression and angiogenic processes

Buanec, Hélène Le; D'Anna, Rossella; Lachgar, A; Zagury, Jean‐François; Bernard, Jacky; Ittelé, D.; d’Alessio, Patrizia; Hallez, Sophie; Giannouli, Christina; Burny, Arsène; Bizzini, B; Gallo, Robert C.; Zagury, Daniel

doi:10.1016/s0753-3322(99)80122-x

Cited by 35 publications

(26 citation statements)

References 31 publications

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“…Consistent with this mode of regulation, we find that Oct-1-binding sites are, in fact, observed at higher frequency in the promoter of genes that are downregulated with the loss of RB. Additionally, it has been observed that HPV-E7 (which downregulates RB activity) has a similar influence on gene expression (Arany and Tyring, 1996;Le Buanec et al, 1999). This finding is consistent with our observations with adenovirus E1A.…”

supporting

confidence: 93%

Loss of the retinoblastoma tumor suppressor: differential action on transcriptional programs related to cell cycle control and immune function

et al. 2007

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Functional inactivation of the retinoblastoma tumor suppressor gene product (RB) is a common event in human cancers. Classically, RB functions to constrain cellular proliferation, and loss of RB is proposed to facilitate the hyperplastic proliferation associated with tumorigenesis. To understand the repertoire of regulatory processes governed by RB, two models of RB loss were utilized to perform microarray analysis. In murine embryonic fibroblasts harboring germline loss of RB, there was a striking deregulation of gene expression, wherein distinct biological pathways were altered. Specifically, genes involved in cell cycle control and classically associated with E2F-dependent gene regulation were upregulated via RB loss. In contrast, a program of gene expression associated with immune function and response to pathogens was significantly downregulated with the loss of RB. To determine the specific influence of RB loss during a defined period and without the possibility of developmental compensation as occurs in embryonic fibroblasts, a second system was employed wherein Rb was acutely knocked out in adult fibroblasts. This model confirmed the distinct regulation of cell cycle and immune modulatory genes through RB loss. Analyses of ciselements supported the hypothesis that the majority of those genes upregulated with RB loss are regulated via the E2F family of transcription factors. In contrast, those genes whose expression was reduced with the loss of RB harbored different promoter elements. Consistent with these analyses, we found that disruption of E2F-binding function of RB was associated with the upregulation of gene expression. In contrast, cells harboring an RB mutant protein (RB-750F) that retains E2F-binding activity, but is specifically deficient in the association with LXCXE-containing proteins, failed to upregulate these same target genes. However, downregulation of genes involved in immune function was readily observed with disruption of the LXCXE-binding function of RB.Thus, these studies demonstrate that RB plays a significant role in both the positive and negative regulations of transcriptional programs and indicate that loss of RB has distinct biological effects related to both cell cycle control and immune function.

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supporting

confidence: 93%

Loss of the retinoblastoma tumor suppressor: differential action on transcriptional programs related to cell cycle control and immune function

et al. 2007

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“…A few studies have shown that HPV E6/E7 could regulate VEGF expression. [36][37][38] However, the current result indicates that VEGF may also modulate HPV E7 expression.…”

Section: Short-lived Rnai In Hela Cellscontrasting

confidence: 58%

Inhibition of cervical cancer cell growth in vitro and in vivo with dual shRNAs

Payne

Sun

et al. 2010

Cancer Gene Ther

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RNA interference (RNAi)-based gene silencing is widely used in laboratories for gene function studies and also holds a great promise for developing treatments for diseases. However, in vivo delivery of RNAi therapy remains a key issue. Lentiviral vectors have been employed for stable gene transfer and gene therapy and therefore are expected to deliver a stable and durable RNAi therapy. But this does not seem to be true in some disease models. Here, we showed that lentivirus delivered short-hairpin RNA (shRNA) against human papillomavirus (HPV) E6/E7 oncogenes were effective for only 2 weeks in a cervical cancer model. However, using this vector to carry two copies of the same shRNA or two shRNAs targeting at two different but closely related genes (HPV E6 and vascular endothelial growth factor) was more effective at silencing the gene targets and inhibiting cell or even tumor growth than their single shRNA counterparts. The cancer cells treated with dual shRNA were also more sensitive to chemotherapeutic drugs than single shRNA-treated cells. These results suggest that a multi-shRNA strategy may be a more attractive approach for developing an RNAi therapy for this cancer.

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“…Among these genes, TSP-1, maspin and VEGF have also been shown to be regulated by p53 (Ravi et al, 2000;Zou et al, 2000;Harada et al, 2003), whose role in the angiogenic process has been clearly described (Bergers and Benjamin, 2003;Fels and Koumenis, 2005). However, the HPV-16 E7 but not E6 protein strongly enhances the release of angiogenic factors tumor necrosis factor-a (TNF-a), IL-1b and IL-6 by activated macrophages (Le Buanec et al, 1999). These findings sustain the hypothesis that E6 and E7 oncoproteins cooperate to stimulate angiogenesis in HPV-16-infected cells, modulating different pathways involving p53 and pRb.…”

Section: Modulation Of Angiogenesis By Oncoviral Proteins Targeting Rmentioning

confidence: 99%

Involvement of RB gene family in tumor angiogenesis

Gabellini¹,

Bufalo²,

Zupi³

2006

Oncogene

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Angiogenesis, the development of new blood vessels from pre-existing vessels, represents a fundamental step in tumor progression and metastatization. The induction of vasculature is required for growth of the tumor mass, to ensure an adequate supply of oxygen and metabolites to the tumor beyond a critical size. Tumor angiogenesis is a highly regulated process that is controlled physiologically by the tumor microenvironment and genetically by alteration of several oncogenes or tumor suppressor genes. We will focus on recent demonstrations regarding the involvement of the retinoblastoma family proteins (phosphorylated retinoblastoma (pRb), p107 and pRb2/p130) at different levels of the angiogenic process. pRb and its homologs can regulate the expression of pro-and antiangiogenic factors, such as the vascular endothelial growth factor, through an E2F-dependent mechanism. Moreover, pRb is able to modulate also the transcriptional activity of several angiogenesis-related factors like HIF-1, Id2 and Oct-1. pRb2/p130 is required for both differentiation and mobilization of bone marrow-derived endothelial cell precursors and endothelial sprouting from neighboring vessels. The involvement of the pRb pathway in the angiogenesis process has also been demonstrated by different cellular models expressing viral oncoproteins, like human papilloma virus. Moreover, some natural and synthetic compounds demonstrate their antiangiogenetic activity with a mechanism of action involving pRb. Finally, the possible prognostic value of immunohistochemical evaluation of pRb and/or pRb2/p130 expression can represent a useful tool for the characterization of the angiogenic phenotype of specific tumor histotypes.

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HPV-16 E7 but not E6 oncogenic protein triggers both cellular immunosuppression and angiogenic processes

Cited by 35 publications

References 31 publications

Loss of the retinoblastoma tumor suppressor: differential action on transcriptional programs related to cell cycle control and immune function

Loss of the retinoblastoma tumor suppressor: differential action on transcriptional programs related to cell cycle control and immune function

Inhibition of cervical cancer cell growth in vitro and in vivo with dual shRNAs

Involvement of RB gene family in tumor angiogenesis

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