Papillomavirus E2 induces senescence in HPV-positive cells via pRB- and p21CIP-dependent pathways

Wells, Susanne I.

doi:10.1093/emboj/19.21.5762

Cited by 191 publications

(202 citation statements)

References 45 publications

(83 reference statements)

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“…58 HPVs interfere with both pathways through the activity of the viral E6 and E7 oncoproteins, 3 and reactivation of p53 and pRb activities after E6/E7 inhibition is linked to senescence induction. [35][36][37]57 This reconstitution of p53, as also observed under our experimental conditions, could affect exosome release as p53 can stimulate the TSAP6 and CHMP4C genes, which both enhance exosome formation by unknown mechanisms. [38][39][40][41] In line with this possibility, we found that the enhanced intracellular p53 levels on E6/E7 inhibition were linked to increased expression of both TSAP6 and CHMP4C in HeLa cells.…”

Section: Infectious Causes Of Cancersupporting

confidence: 72%

Silencing of human papillomavirus (HPV) E6/E7 oncogene expression affects both the contents and the amounts of extracellular microvesicles released from HPV‐positive cancer cells

Honegger

Leitz

Bulkescher

et al. 2013

Intl Journal of Cancer

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The human papillomavirus (HPV) E6/E7 oncogenes play a crucial role in the HPV-induced carcinogenesis. In this study, the authors investigated whether silencing of endogenous HPV E6/E7 expression may influence the contents or amounts of extracellular microvesicles (eMVs) released from HPV-positive cancer cells. It was found that eMVs secreted from HeLa cells are enriched for Survivin protein. RNA interference studies revealed that maintenance of both intracellular and microvesicular Survivin amounts was strongly dependent on continuous E6/E7 expression. This indicates that intracellular HPV activities are translated into visible alterations of protein contents in eMVs. Besides Survivin, eMVs from HeLa cells contain additional members of the inhibitor of apoptosis protein (IAP) family (XIAP, c-IAP1 and Livin). In contrast, no evidence for the presence of the HPV E6 and E7 oncoproteins in eMVs was obtained. Moreover, it was found that silencing of HPV E6/E7 expression led to a significant increase of exosomes-representing eMVs of endocytic origin-released from HeLa cells. This effect was associated with the reinduction of p53, stimulation of the p53 target genes TSAP6 and CHMP4C that can enhance exosome production and induction of senescence. Taken together, these results show that silencing of HPV E6/E7 oncogene expression profoundly affects both the composition and amounts of eMVs secreted by HPV-positive cancer cells. This indicates that HPVs can induce molecular signatures in eMVs that may affect intercellular communication and could be explored for diagnostic purposes.Specific types of human papillomaviruses (HPVs), such as HPV16 and HPV18, cause cervical cancer and are closely linked to the development of additional human malignancies in the oropharyngeal and anogenital regions. 1 The viral E6 and E7 oncoproteins are crucial both for the HPV-associated induction of transformation and for the maintenance of the tumorigenic phenotype of HPV-positive cervical cancer cells. 2,3 E6 and E7 dysregulate intracellular pathways involved in the control of cellular proliferation, apoptosis and genetic stability. For example, E6 induces the proteolytic degradation of the p53 tumor suppressor protein 4 and stimulates telomerase activity, 5 whereas E7 interferes with the activity of the retinoblastoma tumor suppressor protein, pRb, and other pocket proteins. 6 In contrast to the increasing understanding of the intracellular activities of the viral E6/E7 oncogenes, surprisingly little is known about possible effects on the intercellular communication of HPV-positive cancer cells.Extracellular microvesicles (eMVs) include exosomes that are small vesicles (50-100 nm in diameter) of endosomal origin secreted by a variety of cells, including tumor cells. 7 Exosomes have recently gained much interest in oncology, particularly due to three properties: (i) exosomes secreted from tumor cells can suppress the immune response toward the tumor, 8,9 (ii) tumor cell-derived exosomes can accelerate tumor growth and invasiveness by horizon...

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Section: Infectious Causes Of Cancersupporting

confidence: 72%

Silencing of human papillomavirus (HPV) E6/E7 oncogene expression affects both the contents and the amounts of extracellular microvesicles released from HPV‐positive cancer cells

Honegger

Leitz

Bulkescher

et al. 2013

Intl Journal of Cancer

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“…E6/E7 transcription from integrated HPV18 genomes can be specifically downregulated via the introduction of E2, a viral gene that is usually disrupted in cervical cancer. Consequences of E2 expression and reactivation of cellular E6/E7 targets have been characterized extensively, and include cell-cycle arrest and subsequent senescence induction Wells et al, 2000). We previously described the transcriptome signature of senescing HPV18-positive HeLa cervical cancer cells using Affymetrix microarrays and a temperature-sensitive E2 protein (Wells et al, 2003).…”

Section: Resultsmentioning

confidence: 99%

Coordinate regulation of Fanconi anemia gene expression occurs through the Rb/E2F pathway

et al. 2008

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Fanconi anemia (FA) is a genome instability syndrome that is characterized by progressive bone marrow failure and a high risk of cancer. FA patients are particularly susceptible to leukemia as well as squamous cell carcinomas (SCCs) of the head and neck, anogenital region and skin. Thirteen complementation groups and the corresponding FA genes have been identified, and their protein products assemble into nuclear core complexes during DNA-damage responses. Much progress has been made in our understanding of post-translational FA protein modifications and physical interactions. By contrast, little is known about the control of protein availability at the level of transcription. We report here that multiple FA proteins were downregulated during the proliferative arrest of primary human keratinocytes and HeLa cells, and that the observed regulation was at a transcriptional level. Proliferative stimuli such as expression of HPV16 E7 as well as E2F1 overexpression in primary cells resulted in coordinate FA upregulation. To define the underlying mechanism, we examined the endogenous FANCD2 promoter, and detected regulated binding of members of the E2F/Rb family in chromatin immunoprecipitation assays. Finally, a 1 kb promoter fragment was sufficient to confer E2F/Rb regulation in reporter assays. Taken together, our data demonstrate FA gene co-regulation in synchrony with the cell cycle and suggest that deregulated expression of individual FA genes-in addition to FA gene mutation-may promote FA-related human cancer.

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“…Therefore, the F47R-induced senescence pathway appears to be rather distinct than the bovine papillomavirus E2-induced senescence pathway. It was shown earlier that overexpression of p21 CIP by itself could induce senescence in HeLa cells (Wells et al, 2000). In E6 F47R-expressing cells, the sustained activation of p53 signaling pathway and in particular of its target, p21 CIP , may be largely involved in the induction of senescence.…”

Section: Hpv16 E6 Mutant and Cellular Senescence T Ristriani Et Almentioning

confidence: 87%

“…For instance, the transcriptional repression of E6/E7 gene promoter through bovine papillomavirus E2 protein led to reactivation of p53 and pRb pathways and to senescence of HeLa cells (Wells et al, 2000;Horner et al, 2004). Indeed, the repression of 18E7 alone in HeLa cells by expression of the bovine papillomavirus E2 protein induces senescence response that requires activation of endogenous pRB family members but not the p53 pathway (Johung et al, 2007).…”

Section: Hpv16 E6 Mutant and Cellular Senescence T Ristriani Et Almentioning

confidence: 99%

“…In these studies, selective E6 inhibition was found to induce cell growth arrest accompanied in some cases by apoptosis. By contrast, senescence was observed upon combined repression of both E6 and E7 expression mediated either by RNA interference (Hall and Alexander, 2003) or by ectopic expression of the bovine papillomavirus E2 protein, a transcriptional repressor of E6/E7 promoter (Wells et al, 2000;Lee et al, 2002;Horner et al, 2004).…”

Section: Introductionmentioning

confidence: 97%

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A single-codon mutation converts HPV16 E6 oncoprotein into a potential tumor suppressor, which induces p53-dependent senescence of HPV-positive HeLa cervical cancer cells

et al. 2008

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High-risk mucosal human papillomaviruses (HPV), mainly HPV16 and HPV18, are implicated in cervical carcinogenesis. HPV16 E6 oncoprotein binds and often targets for degradation numerous cell proteins, including the tumor suppressor p53 and several PDZ domain proteins. Here, we show that a single-point mutation, F47R, is sufficient to convert the HPV16 E6 oncoprotein into a suppressor of HPV-positive HeLa cervical cancer cells proliferation. The E6 F47R mutant is defective for polyubiquitination and subsequent degradation of p53. When expressed in HPV-positive cervical cancer cells, E6 F47R acts as a dominant negative mutant by counteracting the p53 degradation activity of endogenous E6 and restoring high p53 protein levels. Moreover, the prolonged expression of E6 F47R leads to suppression of HeLa cells proliferation through the induction of premature senescence. This phenotype is independent on the PDZ-binding activity of E6. F47R-senescent HeLa cells exhibit a sustained expression of p53, hMDM2 and p21 CIP proteins and a reduced expression of endogenous HPV18 E6 protein. Finally, small interfering RNAs directed against p53 counteract the effect of E6 F47R expression, indicating that E6 F47R-induced cellular senescence is strongly dependent on p53 signaling pathway.

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Papillomavirus E2 induces senescence in HPV-positive cells via pRB- and p21CIP-dependent pathways

Cited by 191 publications

References 45 publications

Silencing of human papillomavirus (HPV) E6/E7 oncogene expression affects both the contents and the amounts of extracellular microvesicles released from HPV‐positive cancer cells

Silencing of human papillomavirus (HPV) E6/E7 oncogene expression affects both the contents and the amounts of extracellular microvesicles released from HPV‐positive cancer cells

Coordinate regulation of Fanconi anemia gene expression occurs through the Rb/E2F pathway

A single-codon mutation converts HPV16 E6 oncoprotein into a potential tumor suppressor, which induces p53-dependent senescence of HPV-positive HeLa cervical cancer cells

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