HPV-16 oncogenes E6 and E7 are mutagenic in normal human oral keratinocytes

Li, Xuan; Han, Steve; Baluda, M A; Park, No-Hee

doi:10.1038/sj.onc.1201078

Cited by 45 publications

(39 citation statements)

References 19 publications

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“…These results show that, in contrast to previous reports investigating the in¯uence of high risk E6 on gadd45 expression in experimental cell systems (Gujuluva et al, 1994;Shin et al, 1996;Zhan et al, 1996;Liu et al, 1997), gadd45 can be clearly induced in tumor-derived HPV-positive cancer cells by several genotoxic agents. We therefore compared the regulation of gadd45 expression in human foreskin keratinocytes immortalized by retroviral vectors expressing the HPV16 E6, HPV16 E7, or HPV16 E6/E7 genes, respectively, from the CMV promoter (Whitaker and zur Hausen, manuscript in preparation).…”

Section: Resultscontrasting

confidence: 94%

“…Expression of HPV16 E6 from the heterologous CMV promoter in the p53 wildtype cell lines MCF-7 and RKO completely abolished gadd45 induction following g-irradiation (Zhan et al, 1996). Moreover, ectopic expression of HPV16 E6 after infection with retroviral vectors completely abolished gadd45 induction in oral keratinocytes following genotoxic stress (Liu et al, 1997). These results implied that, in the process of viral carcinogenesis, HPVs follow the strategy to inactivate the gadd45 pathway via E6-mediated inhibition of p53.…”

Section: Discussionmentioning

confidence: 82%

“…These ®ndings are in contrast with several studies expressing the HPV E6 oncogene in other cell types and/or from heterologous promoters. For example, human oral keratinocytes, immortalized by stably expressing the HPV16 or HPV18 E6/E7 genes from cloned viral genomes, showed severe defects in the gadd45 response and exhibited a greatly reduced induction, or no induction at all, of gadd45 mRNA levels after DNA damage (Gujulova et al, 1994;Shin et al, 1996;Liu et al, 1997). Expression of HPV16 E6 from the heterologous CMV promoter in the p53 wildtype cell lines MCF-7 and RKO completely abolished gadd45 induction following g-irradiation (Zhan et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, oral keratinocytes ectopically expressing the viral E6 oncogene from a retroviral vector exhibited a complete loss of gadd45 induction (Liu et al, 1997). This suggested that E6-mediated inhibition of gadd45 induction may play a crucial role for HPV-associated carcinogenesis.…”

Section: Introductionmentioning

confidence: 97%

“…The E6 oncoprotein has been shown to induce the degradation of p53 and to inhibit the activity of p53 as a transcription factor (reviewed in Hoppe-Seyler and Sche ner, 1997). Moreover, ectopic expression of high risk E6 protein in various cell types blocked p53-associated cellular responses to DNA damage, such as activation of the p53 target gene p21 WAF1 , cell cycle arrest in G1, or induction of apoptosis (Kessis et al, 1993;Foster et al, 1994;Liu et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

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Induction of the p53-target gene GADD45 in HPV-positive cancer cells

et al. 1999

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The E6 oncoprotein of human papillomaviruses (HPVs) has the potential to functionally antagonize p53. In several experimental model systems, ectopic expression of E6 can block the genotoxic induction of the growth inhibitory p53 target gene gadd45, suggesting that the inactivation of this pathway may play a major role for HPV-associated cell transformation. Here, we investigated whether this re¯ects the regulation of gadd45 expression in carcinoma-derived HPV-positive cells. We found that the gadd45 gene is e ciently induced by mitomycin C, cisplatin, and UV irradiation in a series of HPV-positive cervical cancer cell lines. Moreover, clear induction of gadd45 gene expression was also observed following treatment with g-irradiation, a pathway that is strictly dependent on functional p53. This contrasted with ®ndings in human foreskin keratinocytes experimentally immortalized by expressing the HPV16 E6, E7, or E6/E7 oncogenes from the heterologous CMV promoter, where expression of the E6 gene was linked to a lack of gadd45 induction following g-irradiation.These results indicate (1) that the tumorigenic phenotype of HPV-positive cancer cells is not linked to an inability to induce the gadd45 gene following DNA damage, (2) that experimental model systems in which the E6 gene is expressed ectopically and/or in a di erent cellular context do not necessarily re¯ect the regulation of p53-associated pathways in HPV-positive cancer cells and (3) that a pathway strictly depending on functional p53 is inducible in HPV-positive cancer cells, providing direct evidence that the endogenous p53 protein in these cells is competent to activate a cellular target gene, despite coexpression of the viral E6 oncogene.

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Section: Resultscontrasting

confidence: 94%

Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Induction of the p53-target gene GADD45 in HPV-positive cancer cells

et al. 1999

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Human papillomavirus type 16 E6 and HPV-16 E6/E7 sensitize human keratinocytes to apoptosis induced by chemotherapeutic agents: Roles of p53 and caspase activation

2000

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We and others have previously reported that human papillomavirus (HPV)-16 E6 protein expression sensitizes certain cell types to apoptosis. To confirm that this sensitization occurred in HPV's natural host cells, and to explore the mechanism(s) of sensitization, we infected human keratinocytes (HKCs) with retroviruses containing HPV-6 E6, HPV-16 E6, HPV-16 E7, or HPV-16 E6/E7. Apoptosis was monitored by DNA fragmentation gel analysis and direct observation of nuclei in cells stained with DAPI. Exposure of HKCs to etoposide, cisplatin, mitomycin C (MMC), atractyloside, and sodium butyrate, resulted in a time and dose-dependent induction of apoptosis. Expression of HPV-16 E6 and HPV-16 E6/E7, but not HPV-6 E6 or HPV-16 E7, enhanced the sensitivity of HKCs to cisplatin-, etoposide- and MMC-, but not atractyloside- or sodium butyrate-induced apoptosis. Expression of both HPV-16 E6 and HPV-16 E6/E7 decreased, but did not abolish, p53 protein levels relative to normal HKCs, and resulted in cytoplasmic localization of wt p53. P53 induction occurred in HPV-16 E6 and HPV-16 E6/E7 expressing cells after exposure to cisplatin or MMC, though never to levels found in normal untreated HKCs. P21 levels were decreased in HPV-16 E6 and HPV-16 E6/E7 expressing HKCs, and no induction of p21 was seen in these cells following exposure to cisplatin or MMC. Caspase-3 activity was found to be elevated in HPV-16 E6-expressing HKCs following exposure to cisplatin and MMC as documented by fluorometric and Western Blot analysis. Expression of wt CrmA or treatment of HPV-16 E6 expressing HKCs with the caspase-3 inhibitor DEVD.fmk prevented HPV-16 E6-induced sensitization in HKCs. These results suggest that HPV-16 E6 and HPV-16 E6/E7 expression sensitizes HKCs to apoptosis caused by cisplatin, etoposide and MMC, but not atractyloside or sodium butyrate. The data also suggest that wt p53 and caspase-3 activity are required for HPV-16 E6 and HPV-16 E6/E7-induced sensitization of HKCs to DNA damaging agents.

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The development of bladder tumors and contralateral upper urinary tract tumors after primary transitional cell carcinoma of the upper urinary tract

Kang

Hsieh

et al. 2003

Cancer

223

152

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A four objective optimization framework for preferential crystallization of D‐L threonine solution is presented. The objectives are maximization of average crystal size and productivity, and minimization of batch time and the coefficient of variation at the desired purity while respecting design and operating constraints. The cooling rate, enantiomeric excess of the preferred enantiomer, and the mass of seeds are used as the decision variables. The optimization problem is solved by using adaptation of the nondominated sorting genetic algorithm. The results obtained clearly distinguish different regimes of interest during preferential crystallization. The multi‐objective analysis presented in this study is generic and gives a simplified picture in terms of three zones of operations obtained because of relative importance of nucleation and growth. Such analysis is of great importance in providing better insight for design and decision making, and improving the performance of the preferential crystallization that is considered as a promising future alternative to chromatographic separation of enantiomers. © 2009 American Institute of Chemical Engineers AIChE J, 2009

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HPV-16 oncogenes E6 and E7 are mutagenic in normal human oral keratinocytes

Cited by 45 publications

References 19 publications

Induction of the p53-target gene GADD45 in HPV-positive cancer cells

Induction of the p53-target gene GADD45 in HPV-positive cancer cells

Human papillomavirus type 16 E6 and HPV-16 E6/E7 sensitize human keratinocytes to apoptosis induced by chemotherapeutic agents: Roles of p53 and caspase activation

The development of bladder tumors and contralateral upper urinary tract tumors after primary transitional cell carcinoma of the upper urinary tract

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