E6 and E7 Oncoproteins Induce Distinct Patterns of Chromosomal Aneuploidy in Skin Tumors from Transgenic Mice

Schaeffer, Anthony J.; Nguyen, Marie L.; Liem, Amy; Lee, Denis; Montagna, Cristina; Lambert, Paul F.; Ried, Thomas; Difilippantonio, Michael J.

doi:10.1158/0008-5472.can-03-0124

Cited by 46 publications

(37 citation statements)

References 62 publications

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“…WT tumors that were used in the prior study analysis (25) and found that early and late passages show the same cytogenetic changes as described previously (data not shown). Although CGH analysis of DNA extracted directly from the tumor mass avoids the potential concern for tissue culture artifacts, it raises the concern that cytogenetic abnormalities might be missed if the fractional content of the tumor cell type over normal and/or stromal cells is insufficient.…”

Section: Discussionsupporting

confidence: 67%

“…These include K-ras, ephrin receptors B6 and A1, and transforming growth factor-a (TGF-a). K-ras, a commonly mutated protein in cancer, is an interesting target; however, in our previous studies, no up-regulation of this gene was observed in the K14E6 WT carcinomas (25). The ephrin receptors B6 and A1 are part of the receptor tyrosine kinase family of ephrin receptors.…”

Section: Discussionmentioning

confidence: 88%

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Two Distinct Activities Contribute to Human Papillomavirus 16 E6's Oncogenic Potential

2005

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High-risk human papillomaviruses, such as HPV16, cause cervical cancers, other anogenital cancers, and a subset of head and neck cancers. E6 and E7, two viral oncogenes expressed in these cancers, encode multifunctional proteins best known for their ability to bind and inactivate the tumor suppressors p53 and pRb, respectively. In skin carcinogenesis experiments using E6 transgenic (K14E6 WT ) mice, HPV16 E6 was found to contribute to two distinct stages in skin carcinogenesis: promotion, a step involved in the formation of benign papillomas, and progression, the step involved in the malignant conversion of benign tumors to frank cancer. In this study, we compared the tumorigenic properties of K14E6 WT mice with those of K14E6 D146-151 mice, which express a mutant form of E6 that cannot bind a family of cellular proteins known as PDZ domain proteins but retains the ability to inactivate p53. In skin carcinogenesis experiments, the K14E6 D146-151 transgene failed to contribute to the promotion stage of skin carcinogenesis but retained the ability to contribute to the progression stage. Cytogenetic analysis indicated that, although gains of chromosome 6 are consistently seen in tumors arising on K14E6 WT mice, they are infrequently seen in tumors arising on K14E6 D146-151 mice. This observation supports the premise that the nature of cancer development in these two mouse strains is distinct. Based on these studies, we conclude that E6 contributes to cancer through its disruption of multiple cellular pathways, one of which is mediated through its interaction with PDZ domain partners and the other through E6's inactivation of p53. (Cancer Res 2005; 65(18): 8266-73)

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Section: Discussionsupporting

confidence: 67%

Section: Discussionmentioning

confidence: 88%

Two Distinct Activities Contribute to Human Papillomavirus 16 E6's Oncogenic Potential

2005

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“…Studies are in progress to investigate this in raft culture models of HPV infection. However, these studies are particularly intriguing when one considers the effects of E6 and E7 upon mitosis, where both have been shown to separately induce mitotic abnormalities when stably expressed in cultured cell lines or cells derived from transgenic mice (17,38,45). Further dissection of the role of each protein showed that when each protein is transiently expressed, only E7 results in immediate chromosomal abnormalities (15,16).…”

Section: Discussionmentioning

confidence: 99%

Regulation of Human Papillomavirus Type 16 E7 Activity through Direct Protein Interaction with the E2 Transcriptional Activator

Gammoh

Grm

Massimi

et al. 2006

J Virol

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In order to ensure a productive life cycle, human papillomaviruses (HPVs) require fine regulation of their gene products. Uncontrolled activity of the viral oncoproteins E6 and E7 results in the immortalization of the infected epithelial cells and thus prevents the production of mature virions. Ectopically expressed E2 has been shown to suppress transcription of the HPV E6 and E7 region in cell lines where the viral DNA is integrated into the host genome, resulting in growth inhibition. However, it has been demonstrated that growth control of these cell lines can also occur independently of HPV E2 transcriptional activity in high-risk HPV types. In addition, E2 is unable to suppress transcription of the same region in cell lines derived from cervical tumors that harbor only episomal copies of the viral DNA. Here we show that HPV type 16 (HPV-16) E2 is capable of inhibiting HPV-16 E7 cooperation with an activated ras oncogene in the transformation of primary rodent cells. Furthermore, we demonstrate a direct interaction between the E2 and E7 proteins which requires the hinge region of E2 and the zinc-binding domain of E7. These viral proteins interact in vivo, and E2 has a marked effect upon both the stability of E7 and its cellular location, where it is responsible for recruiting E7 onto mitotic chromosomes at the later stages of mitosis. These results demonstrate a direct role for E2 in regulating the function of E7 and suggest an important role for E2 in directing E7 localization during mitosis.Human papillomaviruses (HPVs) are a large family of small, double-stranded DNA viruses. They infect cutaneous and mucosal epithelial tissue at different anatomical locations, resulting in a variety of clinical symptoms ranging from benign warts to invasive genital cancers (13,29). Infection with the high-risk types, most commonly HPV type 16 (HPV-16) and HPV-18, has been associated with the development of more than 99% of cervical cancer cases. The tumorigenicity of HPV is dependent on the activity of two virally encoded oncoproteins, E6 and E7. These bind at a high affinity and disrupt the function of p53 (46) and the retinoblastoma tumor suppressor protein pRB (6, 20), respectively. While E6 plays a role in inhibiting apoptosis and interfering with cell adhesion and polarity (30), E7 acts by driving S-phase progression, regulating gene expression, and interfering with the activities of cyclins and cyclin-dependent kinases (23). In addition to inactivating the function of pRB, other cellular targets of E7 include the TATA box-binding protein (TBP) (31), TBP-associated factors (35), members of the AP-1 transcription factor family (2), and histone deacetylases (7). E7 is a small phosphoprotein that shares some sequence homology with the adenovirus E1a protein and the simian virus 40 large T antigen (8). E7 is 98 amino acids in length and contains a zinc-binding domain in the C-terminal region whose structural integrity is necessary for the activity of E7 (2, 26). While both E6 and E7 cooperate to induce immortalization o...

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“…These observations have led to development of animal models of virus-induced epithelial cell carcinomas for understanding oncogenic mechanisms in susceptible tissues. Transgenic (TR) mice expressing E6 or E7 protein of high-risk Human papillomaviruses (HPVs) or the SV40 Large T-Antigen (SV40 T-Ag) reveal that viral oncogenes induce epithelial cell cancers by interfering with mechanisms that regulate proliferation and programmed death of epithelial cells Schaeffer et al, 2004;Schreiber et al, 2004). Although significant in-roads have been made in development of anticancer agents, few therapies with proven efficacy are available for highly aggressive epithelial cell carcinomas and for majority of these patients, prognosis following diagnosis is poor (Vilchez and Butel, 2004;Young and Rickinson, 2004;Hughes, 2005).…”

Section: Introductionmentioning

confidence: 99%

Interferon-γ induces regression of epithelial cell carcinoma: critical roles of IRF-1 and ICSBP transcription factors

Egwuagu

et al. 2006

Oncogene

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We have developed an epithelial cell carcinoma model for studying efficacy of IFNc gene therapy and have identified components of IFNc-signaling pathway responsible for its direct anti-tumor actions. The tumor results from ectopic expression of SV40 Large T-Antigen (SV40 T-Ag) oncogene in lens of transgenic mouse (aT3) and complete regression of the tumor is induced by targeting expression of IFNc into malignant lens cells. Inflammatory cells are absent in lens of aT3 or DT (co-expressing IFNc and SV40-T-Antigen) mice and the transformed lens cells are non-immunogenic, suggesting non-involvement of immunologic cells. We show that IFNc has direct growth-inhibitory effects on tumor cells, induces death of tumor cells by apoptosis and that these effects are mediated by two transcription factors, IRF-1 (interferon-regulatory factor-1) and ICSBP (interferon-consensus sequence-binding protein) induced by IFNc. Furthermore, stable transfection with ICSBP or IRF-1 construct inhibits lens carcinoma cell growth by upregulating Caspase-1, p21 WAF1 and p27 expression. In contrast, tumor progression in aT3 lens correlates with inhibition of IRF-1 and ICSBP expression. Our results suggest that IFNc gene therapy maybe effective in malignant diseases for which DNA tumor viruses are etiologic agents and that antitumor actions of IRF-1/ ICSBP can be exploited therapeutically to circumvent adverse clinical effects associated with IFN therapy.

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E6 and E7 Oncoproteins Induce Distinct Patterns of Chromosomal Aneuploidy in Skin Tumors from Transgenic Mice

Cited by 46 publications

References 62 publications

Two Distinct Activities Contribute to Human Papillomavirus 16 E6's Oncogenic Potential

Two Distinct Activities Contribute to Human Papillomavirus 16 E6's Oncogenic Potential

Regulation of Human Papillomavirus Type 16 E7 Activity through Direct Protein Interaction with the E2 Transcriptional Activator

Interferon-γ induces regression of epithelial cell carcinoma: critical roles of IRF-1 and ICSBP transcription factors

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