Human papillomavirus type 16 E7 protein sensitizes cervical keratinocytes to apoptosis and release of interleukin-1α

Iglesias, Maite; Yen, Katy; Gaiotti, Darci; Hildesheim, Allan; Stoler, Mark H.; Woodworth, Craig D.

doi:10.1038/sj.onc.1202054

Cited by 57 publications

(48 citation statements)

References 30 publications

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“…Considering the role of the individual viral oncoproteins, it is known that E7 can stimulate cells to undergo programmed cell death. 52,53 E6 counteracts this process by neutralizing the apoptosis-inducing function of p53. 4 However, CD95 resistance of HPV16 ϩ malignant cells cannot be exclusively attributed to a direct inhibitory effect of the viral E6 oncoprotein on the cell death execution machinery since no correlation between the levels of p53 and the commitment to undergo apoptosis was observed (Fig.…”

Section: Discussionmentioning

confidence: 99%

Differential sensitivity of human papillomavirus type 16+ and type 18+ cervical carcinoma cells to CD95-mediated apoptosis

et al. 2001

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When cervical carcinoma cells were monitored for apoptotic signals, HPV18؉ lines were found to be highly sensitive to agonistic CD95 antibodies or recombinant CD95 ligands after co-exposure with CHX (CD95 S ). In contrast, HPV16؉ cervical carcinoma cells and HPV16-immortalized non-malignant human keratinocytes were CD95-resistant (CD95 R ) under equivalent conditions. Somatic cell hybridization between CD95 S and CD95 R cervical carcinoma cell lines revealed that CD95 sensitivity was a dominant trait, which could be correlated with abundant c-Myc and low Bcl-X L expression. Although CD95 R cervical carcinoma cells expressed even higher levels of p53 and CD95 receptor at the surface, resistance could be attributed to the inability to form a functional DISC, necessary for successful transmission of the apoptogenic response. These data indicate that resistance to apoptotic stimuli represents an important immunological escape mechanism during virus-induced carcinogenesis. © Certain HPV types (e.g., HPV16 and HPV18) are etiologically involved in the development of cervical cancer. 1 Their viral oncogenes, E6 and E7, can induce immortalization of primary human keratinocytes, 2,3 which is accompanied by defined changes of the genetic program. For instance, degradation of p53 by E6 4 and E7-mediated induction of unscheduled DNA synthesis via inappropriate release of the transcription factor E2F from pRb 5 disturb not only cell-cycle control 6 but also DNA repair and chromosomal stability. 7 These effects are apparently not sufficient for the progression from pre-cancerous lesions to invasive cervical cancer. Additional events, such as loss of genetic function 8 and/or abrogation of cross-talk between HPV ϩ keratinocytes and effector cells of the immune system, 9 have to take place to permit malignant transformation.Besides known immunological escape mechanisms, such as down-regulation of MHC class I expression 10 and dysfunctional expression of the chemokine/cytokine pattern, 11,12 accumulation of cervical intra-epithelial cell abnormalities could be favored by disturbances in apoptotic signal transduction. 13 Considering tumor formation simply as a result of a numerical imbalance between cell loss (e.g., through immunological elimination) and cell gain (via uncontrolled proliferation and ignorance of cellular homeostasis signals), 14 there is substantial evidence that certain human pathogenic viruses, e.g., Epstein-Barr virus 15 and human T-cell leukemia virus, 16 can selectively interfere with apoptosis. This is mediated either by ablating pro-apoptotic signals or by enhancing factors that prevent programmed cell death. 17 Apoptosis can be achieved by a variety of external signals, e.g., UV light, 18 nutritional depletion, 19 growth factor withdrawal 20 and chemotherapeutic drugs. 21 Although many reports have described the role of E6 and E7 in apoptosis, 22 the results are somewhat contradictory since the apoptotic response apparently depends on the respective model system and/or the nature of the apoptotic stimulu...

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Section: Discussionmentioning

confidence: 99%

Differential sensitivity of human papillomavirus type 16+ and type 18+ cervical carcinoma cells to CD95-mediated apoptosis

et al. 2001

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“…In contrast, in serum-deprived MEF pRb 7/7 , apoptosis was The DNA fragmentation, characteristic of the internucleosomal cleavage that occurs during apoptosis, was analysed on a 1.8% agarose gel. DNA was extracted from NIH3T3 cells expressing di erent E7 genes as described in Materials and methods Figure 4a, apoptosis was also induced by TNFa/cycloheximide treatment, which has been shown to promote apoptosis in primary human keratinocytes expressing HPV16 E7 gene (Iglesias et al, 1998). HPV16 E7 protein sensitizes MEF pRb +/+ to apoptosis upon TNFa/cycloheximide treatment, whilst in MEF pRb 7/7 cells the percentage of apoptotic cells was similar in absence or presence of E7 protein (Figure 4b).…”

Section: Prb Inactivation Is An Essential Requirement For Hpv16 E7-inmentioning

confidence: 99%

“…As other stimulators of proliferation, the HPV16 E7 protein, besides the ability to deregulate the cell cycle, promotes apoptosis (Pan andGriep, 1994, 1995;White et al, 1994;Puthenveettil et al, 1996;Iglesias et al, 1998;Stoppler et al, 1998). Expression of HPV16 E7 in normal human ®broblasts (NHF) or in human keratinocytes results in a cytocidal response, which is much more evident in the absence of mitogenic signals and displays the typical features of apoptosis .…”

Section: Introductionmentioning

confidence: 99%

Induction of S phase and apoptosis by the human papillomavirus type 16 E7 protein are separable events in immortalized rodent fibroblasts

et al. 2000

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The HPV16 E7 oncoprotein neutralizes several cell cycle checkpoints, favouring the entry of quiescent cells into S phase. This activity is mediated in part by association of E7 with the pocket proteins and consequent activation of E2F transcription factors. In addition, HPV16 E7 protein is able to promote apoptosis. In this study we demonstrate that the ability to induce apoptosis is a common property of E7s belonging to both benign and malignant HPV types. The E7-induced apoptosis is mediated by inactivation of pRb, whilst neutralization of the other two pRB-related proteins, p107 and 130, is not su cient to trigger apoptosis. Moreover, we show that certain point mutations in the conserved region 1 (CR1) of HPV16 E7 abolish the induction of apoptosis without altering the ability to stimulate S phase. Thus, these two E7-mediated cellular events, apoptosis and S phase entry, can be separated in immortalized rodent ®broblasts. Our ®ndings demonstrate that the E7-mediated pRb destabilization is not required for its ability to drive quiescent cells into S phase and to induce apoptosis. Finally, expression of E7 proteins in NIH3T3, which lack a functional p19 ARF , does not lead to p53 accumulation, indicating that the E7 impacts upon additional cellular pathways to promote apoptosis.

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“…The opposing effects of BPV-1 E6 and E7 may be implicated in the life cycle, replication, and maintenance of BPV-1. Recent studies have shown that the high-risk HPV-16 E6 and E7 oncogenes either increase or decrease apoptosis depending on the cell lines and apoptotic stimuli employed (Puthenveettil et al, 1996;Jones et al, 1997;Iglesias et al, 1998;Magal et al, 1998;Rapp and Chen, 1998;Stoppler et al, 1998;Alfandari et al, 1999;Liu et al, 2000b;Mannhardt et al, 2000;Finzer et al, 2002). Interestingly, while normal human diploid fibroblasts that express HPV-16 E7 are highly predisposed to undergo apoptosis in response to growth factor deprivation, they have decreased propensity to undergo apoptosis in response to TNF-and Fas treatment (Jones et al, 1997;Thompson et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Opposing effects of bovine papillomavirus type 1 E6 and E7 genes on Fas-mediated apoptosis

Liu

Gao

et al. 2005

Oncogene

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Programmed cell death (PCD), best exemplified by apoptosis, is a genetically programmed process of cellular destruction that is indispensable for normal development and homeostasis of multicellular organisms. Tumor necrosis factor a (TNF) and related cytokines are employed by host defenses to eliminate virally infected cells through induction of apoptosis. Many viruses have evolved specific gene products to modulate this process. We have recently shown that the bovine papillomavirus type 1 (BPV-1) E6 and E7 genes independently sensitize mouse cells to TNF-induced apoptosis. In this report, we investigated the effect of E6 and E7 expression on Fasmediated apoptosis. In contrast to TNF-mediated apoptosis, E6 and E7 demonstrated opposite effects: while E7 potentiated apoptosis triggered by an agonistic Fas antibody, E6 attenuated the effect. The mitochondrial pathway leading to the activation of caspases appears to be involved in Fas-mediated apoptosis in C127 cells. To further explore the mechanisms by which E6 and E7 modulate Fas-mediated apoptosis, we examined the surface expression of Fas in cells expressing E6 and E7. Significantly, levels of surface Fas expression correlated with the opposing effects of E6 and E7 on Fas-mediated apoptosis. Specifically, while E7 increased the surface expression of Fas, E6 reduced surface Fas expression. Mutational analysis demonstrated a correlation of E6's ability to downregulate surface Fas expression and apoptosis. Since the tumor suppressor p53 can be targeted for degradation by human papillomavirus and has been shown to induce apoptosis by upregulating surface Fas expression, we investigated the role of p53 in BPV-1 E6 and E7 modulation of Fas-mediated apoptosis. Our results demonstrated that the modulatory effects by E6 and E7 could occur in the absence of p53. Interestingly, the reduced Fas protein level on the cell surface is not accompanied by a decrease in total Fas levels in E6-expressing cells. Instead, considerably more Fas protein is found in the cytoplasm of cells expressing E6. These results highlight a novel activity of E6 and E7 that may be involved in viral pathogenesis.

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Human papillomavirus type 16 E7 protein sensitizes cervical keratinocytes to apoptosis and release of interleukin-1α

Cited by 57 publications

References 30 publications

Differential sensitivity of human papillomavirus type 16+ and type 18+ cervical carcinoma cells to CD95-mediated apoptosis

Differential sensitivity of human papillomavirus type 16+ and type 18+ cervical carcinoma cells to CD95-mediated apoptosis

Induction of S phase and apoptosis by the human papillomavirus type 16 E7 protein are separable events in immortalized rodent fibroblasts

Opposing effects of bovine papillomavirus type 1 E6 and E7 genes on Fas-mediated apoptosis

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