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Araldi RP, Assaf SMR, Carvalho RFD, Carvalho MACRD, Souza JMD, Magnelli RF, Módolo DG, Roperto FP, Stocco RDC, Beçak W. Papillomaviruses: a systematic review. Genet Mol Biol 2017; 40:1-21. [PMID: 28212457 PMCID: PMC5409773 DOI: 10.1590/1678-4685-gmb-2016-0128] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2016] [Accepted: 09/28/2016] [Indexed: 12/15/2022] Open
Abstract
In the last decades, a group of viruses has received great attention due to its
relationship with cancer development and its wide distribution throughout the
vertebrates: the papillomaviruses. In this article, we aim to review some of the most
relevant reports concerning the use of bovines as an experimental model for studies
related to papillomaviruses. Moreover, the obtained data contributes to the
development of strategies against the clinical consequences of bovine
papillomaviruses (BPV) that have led to drastic hazards to the herds. To overcome the
problem, the vaccines that we have been developing involve recombinant DNA
technology, aiming at prophylactic and therapeutic procedures. It is important to
point out that these strategies can be used as models for innovative procedures
against HPV, as this virus is the main causal agent of cervical cancer, the second
most fatal cancer in women.
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Affiliation(s)
- Rodrigo Pinheiro Araldi
- Laboratório de Genética, Instituto Butantan, São Paulo, SP, Brazil.,Programa de Pós-graduação Interunidades em Biotecnologia, Instituto de Ciências Biomédicas (ICB), Universidade de São Paulo (USP), São Paulo, SP, Brazil
| | | | | | | | - Jacqueline Mazzuchelli de Souza
- Laboratório de Genética, Instituto Butantan, São Paulo, SP, Brazil.,Programa de Pós-graduação Interunidades em Biotecnologia, Instituto de Ciências Biomédicas (ICB), Universidade de São Paulo (USP), São Paulo, SP, Brazil
| | - Roberta Fiusa Magnelli
- Laboratório de Genética, Instituto Butantan, São Paulo, SP, Brazil.,Programa de Pós-graduação Interunidades em Biotecnologia, Instituto de Ciências Biomédicas (ICB), Universidade de São Paulo (USP), São Paulo, SP, Brazil
| | | | - Franco Peppino Roperto
- Dipartimento di Medicina Veterinaria e Produzioni Animali, Università degli Studi di Napoli Federico II, Napoli, Campania, Italy
| | | | - Willy Beçak
- Laboratório de Genética, Instituto Butantan, São Paulo, SP, Brazil
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Mutagenic Potential ofBos taurus Papillomavirus Type 1 E6 Recombinant Protein: First Description. BIOMED RESEARCH INTERNATIONAL 2015; 2015:806361. [PMID: 26783529 PMCID: PMC4689895 DOI: 10.1155/2015/806361] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/16/2015] [Revised: 10/07/2015] [Accepted: 10/15/2015] [Indexed: 01/16/2023]
Abstract
Bovine papillomavirus (BPV) is considered a useful model to study HPV oncogenic process. BPV interacts with the host chromatin, resulting in DNA damage, which is attributed to E5, E6, and E7 viral oncoproteins activity. However, the oncogenic mechanisms of BPV E6 oncoprotein per se remain unknown. This study aimed to evaluate the mutagenic potential of Bos taurus papillomavirus type 1 (BPV-1) E6 recombinant oncoprotein by the cytokinesis-block micronucleus assay (CBMNA) and comet assay (CA). Peripheral blood samples of five calves were collected. Samples were subjected to molecular diagnosis, which did not reveal presence of BPV sequences. Samples were treated with 1 μg/mL of BPV-1 E6 oncoprotein and 50 μg/mL of cyclophosphamide (positive control). Negative controls were not submitted to any treatment. The samples were submitted to the CBMNA and CA. The results showed that BPV E6 oncoprotein induces clastogenesis per se, which is indicative of genomic instability. These results allowed better understanding the mechanism of cancer promotion associated with the BPV E6 oncoprotein and revealed that this oncoprotein can induce carcinogenesis per se. E6 recombinant oncoprotein has been suggested as a possible vaccine candidate. Results pointed out that BPV E6 recombinant oncoprotein modifications are required to use it as vaccine.
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Chromosome aberrations in cells infected with bovine papillomavirus: comparing cutaneous papilloma, esophagus papilloma, and urinary bladder lesion cells. ISRN ONCOLOGY 2013; 2013:910849. [PMID: 24298391 PMCID: PMC3835608 DOI: 10.1155/2013/910849] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/03/2013] [Accepted: 07/02/2013] [Indexed: 01/16/2023]
Abstract
The majority of malignant cells present genetic instability with chromosome number changes plus segmental defects: these changes involve intact chromosomes and breakage-induced alterations. Some pathways of chromosomal instability have been proposed as random breakage, telomere fusion, and centromere fission. Chromosome alterations in tumor cells have been described in animal models and in vitro experiments. One important question is about possible discrepancies between animal models, in vitro studies, and the real events in cancer cells in vivo. Papillomaviruses are relevant agents in oncogenic processes related to action on host genome. Recently, many reports have discussed the presence of virus DNA in peripheral blood, in humans and in animals infected by papillomaviruses. The meaning of this event is of controversy: possible product of apoptosis occurring in cancer cells, metastasized cancer cells, or active DNA sequences circulating in bloodstream. This study compares chromosome aberrations detected in bovine cells, in peripheral blood cells, and in BPV lesion cells: the literature is poor in this type of study. Comparing chromosome aberrations described in the different cells, a common mechanism in their origin, can be suggested. Furthermore blood cells can be evaluated as an effective way of virus transmission.
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Activation of Cdc2 contributes to apoptosis in HPV E6 expressing human keratinocytes in response to therapeutic agents. J Mol Biol 2007; 374:334-45. [PMID: 17936297 DOI: 10.1016/j.jmb.2007.09.031] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2007] [Revised: 09/01/2007] [Accepted: 09/09/2007] [Indexed: 12/18/2022]
Abstract
Infection with human papillomaviruses (HPV) is strongly associated with the development of cervical cancer. The HPV E6 oncogene induces apoptosis in cervical cancer precursor lesions but the mechanism is poorly understood. While it is expected that inactivation of p53 by E6 should lead to a reduction in apoptosis, E6 also sensitizes cells to apoptosis under some experimental conditions. Here, we demonstrate that expression of E6 in human keratinocytes rendered sensitization to chemotherapeutic agents. The cell death was shown to be by apoptosis involving caspase activation and the mitochondria pathway. To explore mechanisms involved in sensitization of E6 expressing cells to apoptosis, we used a proteomic approach to identify proteins differentially expressed in E6 expressing and control keratinocytes. Among nearly a thousand proteins examined, Cdc2 was demonstrated to be the most dramatically up-regulated protein in E6 expressing cells. p53 degradation appears to be important for the up-regulation of Cdc2 by E6. Using genetic, pharmacologic, and siRNA strategies, a role for Cdc2 in E6 expression-conferred apoptosis was demonstrated. Thus, these results have important therapeutic implications in enhancing the efficacy of chemotherapy.
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Liu Y, Liu Z, Gao H, Zhou Y, Androphy EJ, Chen JJ. Opposing effects of bovine papillomavirus type 1 E6 and E7 genes on Fas-mediated apoptosis. Oncogene 2005; 24:3942-53. [PMID: 15782122 DOI: 10.1038/sj.onc.1208542] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
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 alpha (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 Fas-mediated 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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Affiliation(s)
- Yun Liu
- Department of Medicine, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605-2324, USA
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Abstract
Infection with human papillomaviruses is strongly associated with the development of multiple cancers including esophageal squamous cell carcinoma. The HPV E6 gene is essential for the oncogenic potential of HPV. The regulation of apoptosis by oncogene has been related to carcinogenesis closely; therefore, the modulation of E6 on cellular apoptosis has become a hot research topic recently. Inactivation of the pro-apoptotic tumor suppressor p53 by E6 is an important mechanism by which E6 promotes cell growth; it is expected that inactivation of p53 by E6 should lead to a reduction in cellular apoptosis, numerous studies showed that E6 could in fact sensitize cells to apoptosis. The molecular basis for apoptosis modulation by E6 is poorly understood. In this article, we will present an overview of observations and current understanding of molecular basis for E6-induced apoptosis.
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Affiliation(s)
- Ting-Ting Li
- Institute of Gastroenterology, 15 West Changle Road, Xijing Hospital Xi'an 710032, Shaanxi Province, China
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Gascoyne DM, Kypta RM, Vivanco MDM. Glucocorticoids inhibit apoptosis during fibrosarcoma development by transcriptionally activating Bcl-xL. J Biol Chem 2003; 278:18022-9. [PMID: 12637494 DOI: 10.1074/jbc.m301812200] [Citation(s) in RCA: 62] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Glucocorticoids influence many physiological processes, and in particular apoptosis, often with opposite effects depending on the cell type examined. We found that during fibrosarcoma development there is a strong increase in apoptosis at the tumor stage, which is repressed by dexamethasone to levels observed in normal fibroblasts. The anti-apoptotic Bcl-2 family protein Bcl-x(L) is induced by dexamethasone at the transcriptional level at all stages of fibrosarcoma development. The ligand-activated glucocorticoid receptor (GR) activates the Bcl-x promoter in transient transfection experiments, and GR binds to specific Bcl-x promoter sequences in vitro and in vivo. Furthermore, a GR antagonist abolishes this effect, indicating that Bcl-x(L) induction is mediated by GR. Importantly, exogenous Bcl-x(L) inhibits apoptosis and caspase-3 activity in fibrosarcoma cells to levels found in dexamethasone-treated fibrosarcoma cells. We conclude that Bcl-x(L) is a key target mediating the anti-apoptotic effects of glucocorticoids during fibrosarcoma development. These observations provide further understanding of the molecular basis of glucocorticoid regulation of cell death during tumorigenesis.
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Affiliation(s)
- Duncan M Gascoyne
- Breakthrough Toby Robins Breast Cancer Research Centre, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, United Kingdom
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