RESUMO
This summer marks the 51st anniversary of the DNA tumor virus meetings. Scientists from around the world will gather in Trieste, Italy, to report their latest results and to agree or disagree on the current concepts that define our understanding of this diverse class of viruses. This article offers a brief history of the impact the study of these viruses has had on molecular and cancer biology and discusses obstacles and opportunities for future progress.
Assuntos
Vírus de DNA Tumorais/fisiologia , Biologia Molecular/história , Neoplasias/história , Neoplasias/virologia , Animais , Congressos como Assunto , História do Século XX , História do Século XXI , Humanos , ItáliaRESUMO
Protein phosphatase 2A (PP2A) is a large family of holoenzymes that comprises 1% of total cellular proteins and accounts for the majority of Ser/Thr phosphatase activity in eukaryotic cells. Although initially viewed as constitutive housekeeping enzymes, it is now well established that PP2A proteins represent a family of highly and sophistically regulated phosphatases. The past decade, multiple complementary studies have improved our knowledge about structural and functional regulation of PP2A holoenzymes. In this regard, after summarizing major cellular regulation, this review will mainly focus on discussing a particulate biological strategy, used by various viruses, which is based on the targeting of PP2A enzymes by viral proteins in order to specifically deregulate, for their own benefit, cellular pathways of their hosts. The impact of such PP2A targeting for research in human diseases, and in further therapeutic developments, is also discussed.
Assuntos
Vírus de DNA Tumorais/fisiologia , HIV-1/fisiologia , Proteína Fosfatase 2/antagonistas & inibidores , Proteína Fosfatase 2/metabolismo , Retroviridae/fisiologia , Proteínas Virais/farmacologia , Humanos , Transporte ProteicoRESUMO
Torque teno (TT) viruses have been more frequently reported in malignant biopsies when compared to normal control tissue. The possible contribution of TT virus infection to human carcinogenesis or the potential oncolytic functions of these virus infections are being discussed based on available experimental evidence. The data could suggest an involvement of TT virus infections as an indirect carcinogen by modulating T cell immune responses. Significant oncolytic functions, potentially mediated by the inhibition of nuclear factor (NF)-kappaB transcription factor or by apoptin-like gene activities, are emerging to be less likely.
Assuntos
Transformação Celular Viral , Vírus de DNA Tumorais/fisiologia , Infecções por Vírus de DNA/virologia , Neoplasias/virologia , Torque teno virus/fisiologia , Infecções Tumorais por Vírus/virologia , HumanosRESUMO
Intense study of three families of small tumour viruses with double-stranded DNA genomes, carried out over 50 years, has had a profound impact on biology. The polyomaviruses and papillomaviruses have circular DNA genomes of approximately 5000 and approximately 8000 base-pairs, respectively, and thus encode only a handful of proteins. Adenoviruses have a 32 000-base-pair linear DNA genome, still far smaller than the three billion-base-pair human genome. Members of all three virus families can transform cultured cells to tumorigenicity and cause tumours in experimental animals. Several human papillomaviruses (HPV) and at least one polyomavirus are oncogenic in humans. Early analysis of these viruses, particularly the polyomavirus SV40, led to the development of many powerful experimental tools, including restriction mapping, site-directed mutagenesis, gene transfer, genome-wide sequencing and recombinant DNA. These tools have since been refined and used to study cellular genes, revolutionizing our understanding of biology. These tools were also applied to the viruses themselves. Analysis of the virus life cycle and the effect of these viruses on cells yielded important new insights into many aspects of gene expression, DNA replication, cell biology and carcinogenesis. These studies have also led to vaccination strategies to prevent infection and cancer in humans. This article is part of the theme issue 'Silent cancer agents: multi-disciplinary modelling of human DNA oncoviruses'.
Assuntos
Vírus de DNA Tumorais/fisiologia , Infecções Tumorais por Vírus/virologia , Animais , HumanosRESUMO
To infect mammalian cells, all infectious viruses must cross a common set of biophysical membrane barriers to gain access to the cell. The virus capsid proteins attach to a host cell, become endocytosed, and traffic the viral genome to sites of replication. To do this they must interact with the membrane-confined organelles that control endocytosis, endosomal sorting, processing, and degradation of biological molecules. In this review, we highlight some recent advances in our understanding of the mechanisms that small non-enveloped DNA tumor viruses, such as Human Papillomavirus (HPV) and Polyomaviruses (PyV) employ to attain infectious entry. These viruses exploit different pathways to mediate entry, uncoating and subsequent transport to the nucleus via the Trans Golgi Network (TGN) or the Endoplasmic Reticulum (ER). Understanding how the viral capsid proteins interact with cellular membranous organelles sheds light on the novel ways by which viruses can hi-jack endocytic transport pathways and provides unique insights into how the highly complex machinery controlling cargo fate determination is regulated within the cell.
Assuntos
Membrana Celular/metabolismo , Vírus de DNA Tumorais/fisiologia , Internalização do Vírus , Animais , Endossomos/metabolismo , Humanos , Transporte Proteico , Rede trans-GolgiRESUMO
Studies using the transforming proteins of the small DNA tumor viruses point to the role of the E2F cellular transcription factor in regulating cell cycle specific gene expression. The evidence derived suggests that E2F is controlled by the retinoblastoma gene product and related proteins, including their associated cyclins. Studies using DNA tumor virus products further suggest the existence of additional pathways of cell-cycle activation.
Assuntos
Proteínas de Transporte , Proteínas de Ciclo Celular , Ciclo Celular , Transformação Celular Viral , Vírus de DNA Tumorais/fisiologia , Proteínas de Ligação a DNA , Proteínas Oncogênicas Virais/fisiologia , Fatores de Transcrição/fisiologia , Sequência de Aminoácidos , Animais , Sequência de Bases , Ciclinas/metabolismo , Vírus de DNA Tumorais/genética , Fatores de Transcrição E2F , Humanos , Modelos Biológicos , Dados de Sequência Molecular , Proteínas Oncogênicas Virais/genética , Proteína do Retinoblastoma/fisiologia , Proteína 1 de Ligação ao Retinoblastoma , Fator de Transcrição DP1RESUMO
Viruses have evolved various mechanisms to evade host immunity and ensure efficient viral replication and persistence. Several DNA tumor viruses modulate host DNA methyltransferases for epigenetic dysregulation of immune-related gene expression in host cells. The host immune responses suppressed by virus-induced aberrant DNA methylation are also frequently involved in antitumor immune responses. Here, we describe viral mechanisms and virus-host interactions by which DNA tumor viruses regulate host DNA methylation to evade antiviral immunity, which may contribute to the generation of an immunosuppressive microenvironment during cancer development. Recent trials of immunotherapies have shown promising results to treat multiple cancers; however, a significant number of non-responders necessitate identifying additional targets for cancer immunotherapies. Thus, understanding immune evasion mechanisms of cancer-causing viruses may provide great insights for reversing immune suppression to prevent and treat associated cancers.
Assuntos
Transformação Celular Neoplásica/genética , Transformação Celular Viral , Metilação de DNA , Vírus de DNA Tumorais/fisiologia , Interações Hospedeiro-Patógeno , Evasão da Resposta Imune , Infecções Tumorais por Vírus/genética , Infecções Tumorais por Vírus/virologia , Vírus de DNA Tumorais/classificação , Humanos , Infecções Tumorais por Vírus/complicaçõesRESUMO
Viruses regulate cellular processes to facilitate viral replication. Manipulation of nuclear proteins and pathways by nuclear replicating viruses often causes cellular genome instability that contributes to transformation. The cellular DNA damage response (DDR) safeguards the host to maintain genome integrity, but DNA tumour viruses can manipulate the DDR to promote viral propagation. In this review, we describe the interactions of DNA tumour viruses with the phosphatidylinositol 3-kinase-like protein kinase (PIKK) pathways, which are central regulatory arms of the DDR. We review how signalling through the ataxia telangiectasia mutated (ATM), ataxia telangiectasia and Rad3 related (ATR), and DNA-dependent protein kinases (DNA-PK) influences viral life cycles, and how their manipulation by viral proteins may contribute to tumour formation.This article is part of the themed issue 'Human oncogenic viruses'.
Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/fisiologia , Carcinogênese/genética , Vírus de DNA Tumorais/fisiologia , Proteína Quinase Ativada por DNA/fisiologia , Transdução de Sinais , Proteínas Virais/metabolismo , Dano ao DNA , Reparo do DNA , Humanos , Proteínas QuinasesRESUMO
Productive viral infection requires coordinate regulation of viral and cellular gene expression. Viruses of different classes have evolved different mechanisms to conform to, adapt to and exploit programs of cellular gene expression. Many viral gene products influence and respond to cellular signals that control differentiation and proliferation Transcriptional coactivators are central to the regulation of the expression of genes controlling these events. p300 and CBP are closely related coactivators that regulate the transcription of specific genes, modify chromatin structure and influence cell cycle progression. In this review, the different molecular interactions of proteins encoded by DNA tumor viruses and lentiviruses with these transcriptional coactivators and related cellular proteins are summarized.
Assuntos
Vírus de DNA Tumorais/fisiologia , Lentivirus/fisiologia , Transativadores/metabolismo , Replicação Viral/fisiologia , Animais , Proteína de Ligação a CREB , Transformação Celular Viral , Vírus de DNA Tumorais/genética , Regulação Viral da Expressão Gênica , Histona Acetiltransferases , Humanos , Lentivirus/genética , Camundongos , Proteínas Nucleares/metabolismo , Coativador 3 de Receptor NuclearRESUMO
Virus replication and spreading in a host population depends on highly specific interactions of viral proteins with infected cells, resulting in subversion of multiple cellular signal transduction pathways. For instance, viral proteins cause cell cycle progression of the infected host cell in order to establish a cellular environment favourable for virus replication. Of equal importance for successful virus propagation is virus-mediated attenuation of a host's immune response. Many of the pathways controlling these aspects of cell behaviour are regulated by cellular tyrosine kinases. One particular family of these enzymes, Src family kinases, are involved in processing signals emanating from the plasma membrane upon stimulation by growth factors, by cell-substratum or by cell-cell contact. Two families of DNA viruses, polyoma- and herpesviruses, encode proteins targeted at tyrosine kinases. The middle-T antigens expressed by mouse and hamster polyomavirus associate with and activate Src family tyrosine kinases. Two members of the herpes family of DNA viruses, Epstein-Barr virus (EBV) and herpesvirus saimiri (HVS), encode proteins, LMP2A and Tip, respectively, that associate with cellular tyrosine kinases of the Src and Syk/Zap family. Upon association with these viral proteins, the activity of these tyrosine kinases is changed resulting in altered signal output. Middle-T, LMP2A and Tip are therefore excellent tools to study the regulation of Src family kinases.
Assuntos
Vírus de DNA Tumorais/fisiologia , Transdução de Sinais/fisiologia , Quinases da Família src/fisiologia , AnimaisAssuntos
Vírus de DNA Tumorais/fisiologia , Vírus da Hepatite B/fisiologia , Herpesvirus Humano 4/fisiologia , Neoplasias/etiologia , Papillomaviridae/fisiologia , Animais , Transformação Celular Neoplásica , Transformação Celular Viral , Vírus de DNA Tumorais/genética , Genes Virais , Vírus da Hepatite B/genética , Herpesvirus Humano 4/genética , Humanos , Neoplasias/imunologia , Neoplasias/prevenção & controle , Oncogenes , Papillomaviridae/genética , Infecções Tumorais por Vírus/microbiologiaRESUMO
It is hypothesized that oncogenic viruses (both RNA and DNA tumor viruses) use cellular differentiation switches as part of their mechanism for viral replication. Chemical or radiation-induced carcinogenesis is the result of mutations which also affect these differentiation switches and their cellular controls. A transformed cell is characterized by the uncontrolled and inappropriate expression of embryonic (developmental) sequences. Many of the oncogenic viruses, both RNA and DNA, are lineage- and stage-specific in the cells they can productively infect, in keeping with their means of replication. The interaction between virus and host cellular controls determines whether recognizable neoplasia will result from viral infection.
Assuntos
Diferenciação Celular , Transformação Celular Viral , Vírus de DNA Tumorais/fisiologia , Regulação da Expressão Gênica , Modelos Genéticos , Retroviridae/fisiologia , Animais , Replicação do DNA , Vírus Defeituosos/fisiologia , Genes Reguladores , Vírus Auxiliares/fisiologia , Humanos , Morfogênese , Oncogenes , Replicação ViralAssuntos
Proteínas de Transporte , Proteínas de Ciclo Celular , Ciclo Celular , Vírus de DNA Tumorais/fisiologia , Proteínas de Ligação a DNA , Animais , Ciclo Celular/genética , Ciclo Celular/fisiologia , Replicação do DNA , Fatores de Transcrição E2F , Humanos , Modelos Biológicos , Proteínas Oncogênicas Virais/fisiologia , Proteína do Retinoblastoma/fisiologia , Proteína 1 de Ligação ao Retinoblastoma , Fator de Transcrição DP1 , Fatores de Transcrição/fisiologia , Replicação ViralAssuntos
Vírus de DNA Tumorais/fisiologia , Ubiquitina/metabolismo , Linhagem Celular , Cisteína Endopeptidases/metabolismo , Proteínas do Citoesqueleto/metabolismo , Vírus de DNA Tumorais/genética , Vírus de DNA Tumorais/patogenicidade , Humanos , Modelos Biológicos , Complexos Multienzimáticos/metabolismo , Complexo de Endopeptidases do Proteassoma , Transdução de Sinais , Transativadores/metabolismo , beta CateninaAssuntos
Cromossomos/genética , Replicação do DNA/genética , Fatores de Transcrição/fisiologia , Animais , Subunidade alfa 2 de Fator de Ligação ao Core/fisiologia , Vírus de DNA Tumorais/genética , Vírus de DNA Tumorais/fisiologia , Proteínas de Ligação a DNA , Drosophila melanogaster/genética , Genoma Viral/genética , Humanos , Complexo de Reconhecimento de Origem/fisiologia , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae , Replicação Viral/genéticaAssuntos
Proteínas E1A de Adenovirus/fisiologia , Proteínas de Transporte , Proteínas de Ciclo Celular , Proteínas de Ligação a DNA , Regulação Viral da Expressão Gênica , Transcrição Gênica , Adenoviridae/genética , Adenoviridae/fisiologia , Proteínas Precoces de Adenovirus/fisiologia , Ciclo Celular , Divisão Celular , Vírus de DNA Tumorais/fisiologia , Fatores de Transcrição E2F , Humanos , Proteína 1 de Ligação ao Retinoblastoma , Fator de Transcrição DP1 , Fatores de Transcrição/fisiologiaAssuntos
Transformação Celular Neoplásica , Vírus de DNA Tumorais/fisiologia , Neoplasias/microbiologia , Oncogenes , Retroviridae/fisiologia , Animais , Vírus do Sarcoma Aviário/fisiologia , Neoplasias da Mama/microbiologia , Linfoma de Burkitt/microbiologia , Carcinoma Hepatocelular/etiologia , Transformação Celular Viral , Feminino , Gammaretrovirus/fisiologia , Hepatite B/complicações , Herpesviridae/fisiologia , Doença de Hodgkin/microbiologia , Humanos , Leucemia/microbiologia , Neoplasias Hepáticas , Linfoma/microbiologia , Masculino , Neoplasias Nasofaríngeas/microbiologia , Papillomaviridae/fisiologia , Sarcoma/microbiologia , Neoplasias do Colo do Útero/microbiologiaRESUMO
Viruses have evolved to use cellular pathways to their advantage, including the ubiquitin-proteasome pathway of protein degradation. In several cases, viruses produce proteins that highjack cellular E3 ligases to modify their substrate specificity in order to eliminate unwanted cellular proteins, in particular inhibitors of the cell cycle. They can also inhibit E3 ligase to prevent specific protein degradation or even use the system to control the level of expression of their own proteins. In this review we explore the specific ways that small DNA tumor viruses exploit the ubiquitin-proteasome pathway for their own benefit.