Human Papillomavirus Type 16 E7 Binds to E2F1 and Activates E2F1-driven Transcription in a Retinoblastoma Protein-independent Manner

Hwang, Sun Gwan; Lee, Daeyoup; Kim, Jiyun; Seo, Taegun; Choe, Joonho

doi:10.1074/jbc.m109113200

Cited by 121 publications

(97 citation statements)

References 69 publications

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“…Notably, a recent study has shown that E7 can also interact with E2F-1 in a pRbindependent fashion, thereby augmenting its proapoptotic activity. In this constellation, expression of both proteins in pRb-negative cells resulted in stronger apoptosis than with E2F-1 alone (Hwang et al, 2002). These data are related to our previous observation that pRb degradation and apoptosis occurred only in E7 oncogene-expressing cells, but not in their E6-positive counterparts (Finzer et al, 2001).…”

Section: Discussionsupporting

confidence: 76%

“…In cervical carcinomas, which represent the second most frequent gynecological malignancy worldwide (Pisani et al, 2002), pRb is deregulated by the human papillomavirus (HPV) E7 oncogene, which results in the unscheduled transcriptional activation of E2F target genes (Dyson et al, 1989;Hwang et al, 2002). Since malignant growth arises from the simultaneous occurrence of deregulated cell proliferation and suppressed apoptotic signals (Green and Evan, 2002), it is striking that inhibitors of the histone deacetylase (HDAC) can efficiently revert both of these pathways in HPV-positive cancer cells (Finzer et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

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HDAC inhibitors trigger apoptosis in HPV-positive cells by inducing the E2F–p73 pathway

et al. 2004

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Histone deacetylase (HDAC) inhibitors induce an intrinsic type of apoptosis in human papillomavirus (HPV)-positive cells by disrupting the mitochondrial transmembrane potential (DW m ). Loss of DW m was only detected in E7, but not in E6 oncogene-expressing cells. HDAC inhibition led to a time-dependent degradation of the pocket proteins pRb, p107 and p130, releasing 'free' E2F-1 following initial G1 arrest. Inhibition of proteasomal proteolysis, but not of caspase activity rescued pRb from degradation and functionally restored its inhibitory effect on the cyclin E gene, known to be suppressed by pRb-E2F-1 in conjunction with HDAC1. Using siRNA targeted against p53, E2F-1 still triggered apoptosis by inducing the E2F-responsive proapoptotic a-and b-isoforms of p73. These data may determine future therapeutic strategies in which HDAC inhibitors can effectively eliminate HPVpositive cells by an apoptotic route that does not rely on the reactivation of the 'classical' p53 pathway through a preceding shut-off of viral gene expression.

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Section: Discussionsupporting

confidence: 76%

Section: Introductionmentioning

confidence: 99%

HDAC inhibitors trigger apoptosis in HPV-positive cells by inducing the E2F–p73 pathway

et al. 2004

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“…Meanwhile, the level of E2F1 protein and its activity as determined by c-Myc expression level were reduced upon 2-DG treatment (Fig. 3A), most likely because of the depletion of E7, which has been shown to activate E2F1 either directly (38) or through inactivation of Rb (39). Therefore, the status of these factors is as expected in HeLa cells where E6/E7 proteins were depleted.…”

Section: Repression Of Hpv Early Gene Expression By 2-dg Treatment Hmentioning

confidence: 99%

Down-regulation of Sp1 Activity through Modulation of O-Glycosylation by Treatment with a Low Glucose Mimetic, 2-Deoxyglucose

Kang

Cho

et al. 2003

Journal of Biological Chemistry

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2-Deoxyglucose (2-DG), a nonmetabolizable glucose analogue, blocks glycolysis at the phosphohexose isomerase step and has been frequently used as a glucose starvation mimetic in studies of a wide variety of physiological dysfuctions. However, the effect of 2-DG on protein glycosylation and related signal pathways has not been investigated in depth. In HeLa, an HPV18-positive cervical carcinoma line, 2-DG treatment downregulates human papillomavirus early gene transcription. This down-regulation was also achieved by low glucose supply or hypoxia, suggesting that this is a response commonly modulated by cellular glucose or energy level. We investigated how 2-DG and low glucose affect transcriptional activity. Human papillomavirus gene transcription was only marginally affected by the inhibition of ATP synthesis or the supplementation of pyruvate to 2-DG-treated cells, suggesting that poor ATP generation is involved only to a limited extent. 2-DG treatment also inhibited activation of p21 WAF1 promoter, which is controlled by p53 and/or Sp1. In a reporter assay using p21 WAF1 promoter constructs, 2-DG exerted a strong inhibitory effect on Sp1 activity. DNA binding activity of Sp1 in 2-DG-treated HeLa cells was intact, whereas it was severely impaired in cells incubated in a low glucose medium or in hypoxic condition. Unexpectedly, Sp1 was heavily modified with GlcNAc in 2-DG-treated cells, which is at least partially attributed to the inhibitory effect of 2-DG on N-acetyl-␤-D-glucosaminidase activity. Our results suggest that 2-DG, like low glucose or hypoxic condition, down-regulates Sp1 activity, but through hyper-GlcNAcylation instead of hypo-GlcNAcylation.

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“…This effectively removes one of the main nodes of cell-cycle regulation at this point and facilitates unscheduled progression into S-phase. This is potentiated by the direct binding of E7 to E2F1 with consequent activation of E2F1-drive transcription (Hwang et al, 2002). The role of pRb is not limited to the G1/S boundary of the cell cycle.…”

mentioning

confidence: 99%

Induction of tetrasomy by human papillomavirus type 16 E7 protein is independent of pRb binding and disruption of differentiation

2004

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We have demonstrated previously that high-risk human papillomaviruses (HPVs) induce tetrasomy in low-grade squamous intraepithelial lesions of the cervix. In this study we show that the E6 and E7 genes of high-risk HPV-16, but not those of low-risk HPV-6, are independently able to induce tetrasomy when constitutively expressed in proliferating monolayer cultures of primary human keratinocytes. Of seven HPV-16 E7 mutants analysed (H2P, D6 -10, D21 -24, C24G, S31G/S32G, A50S and S71I), five were severely impaired in their ability to induce tetrasomy in monolayer and raft culture. Only mutant C24G induced tetrasomy to levels comparable with wild-type E7 in monolayer and raft culture. This mutant shows strongly reduced binding to the retinoblastoma gene product pRb. The casein kinase II phosphorylation defective mutant S31G/S32G induced tetrasomy to levels comparable with wildtype E7 in raft culture, but not in monolayer culture, and induction of tetrasomy did not correlate with raft morphology. These results indicate that pRb protein binding is not required for HPV-16 E7 associated tetrasomy and that tetrasomy is not directly related to the ability of this protein to disrupt keratinocyte differentiation. (Walboomers et al, 1999). Particular HPV types, most notably HPV 16 and 18, predominate in this association and are thus referred to as highrisk types. In previous studies we have shown that basal cell tetrasomy occurs in low-grade squamous intraepithelial lesions of the cervix (SILs) infected with high-risk HPVs but not in those infected with low-risk HPVs (Southern et al, 1997). Tetrasomic cells contain four separate copies of each chromosome instead of two. In normal cells, replicated chromosomes remain as tightly associated sister chromatid pairs until mitosis. Sister chromatid separation is stringently regulated and only occurs after each replicated chromosome has become aligned on the mitotic spindle. In tetrasomic cells it would seem that the sister chromatids have become separated but that a subsequent step in mitosis has arrested or failed. Such failures in mitosis can lead to genetic instability and are of cardinal importance in the cancer process.HPVs encode two small proteins, E6 and E7 that act as potent cell-cycle dysregulators and are able to drive infected cells into Sphase to allow replication of viral DNA. In a productive HPV infection the viral genome is maintained episomally and E6 and E7 are expressed at low levels under viral cis-and trans-acting control. During neoplastic progression the expression of E6 and E7 is de-repressed, usually as a result of integration of the viral DNA into the host genome. Expression of high-risk E6 and E7 proteins can immortalise primary human epithelial cells in vitro (HawleyNelson et al, 1989) and both proteins bind to numerous cellular target proteins (Kuhne and Banks, 1999; Zwerschke and JansenDurr, 2000), several of which are also targets of adenovirus and SV40 early proteins.The best studied interaction of E7 is that with pRb (Helt and Galloway, 2003). In ...

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Human Papillomavirus Type 16 E7 Binds to E2F1 and Activates E2F1-driven Transcription in a Retinoblastoma Protein-independent Manner

Cited by 121 publications

References 69 publications

HDAC inhibitors trigger apoptosis in HPV-positive cells by inducing the E2F–p73 pathway

HDAC inhibitors trigger apoptosis in HPV-positive cells by inducing the E2F–p73 pathway

Down-regulation of Sp1 Activity through Modulation of O-Glycosylation by Treatment with a Low Glucose Mimetic, 2-Deoxyglucose

Induction of tetrasomy by human papillomavirus type 16 E7 protein is independent of pRb binding and disruption of differentiation

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