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1.
PLoS Pathog ; 11(1): e1004581, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25607954

RESUMO

KSHV is the causative agent of Kaposi sarcoma (KS), a spindle-shaped endothelial cell neoplasm accompanied by an inflammatory infiltrate. To evaluate the role of KSHV vFLIP in the pathogenesis of KS, we constructed mice with inducible expression of vFLIP in endothelial cells. Abnormal cells with endothelial marker expression and fusiform appearance were observed in several tissues reminiscent of the spindle cells found in KS. Serum cytokines displayed a profound perturbation similar to that described in KSHV inflammatory cytokine syndrome (KICS), a recently described clinical condition characterized by elevated IL6 and IL10. An increased myeloid component with suppressive immune phenotype was found, which may contribute to functional changes in the microenvironment and cellular heterogeneity as observed in KS. These mice represent the first in vivo demonstration that vFLIP is capable of inducing vascular abnormalities and changes in host microenvironment with important implications for understanding the pathogenesis and treating KSHV-associated diseases.


Assuntos
Células Endoteliais/metabolismo , Células Endoteliais/patologia , Inflamação/patologia , Células Mieloides/fisiologia , Proteínas Virais/genética , Animais , Linhagem da Célula/genética , Microambiente Celular/genética , Microambiente Celular/imunologia , Células Endoteliais/imunologia , Inflamação/genética , Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Transgênicos , Fenótipo , Sarcoma de Kaposi/virologia , Proteínas Virais/metabolismo
2.
Blood ; 125(20): e14-22, 2015 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-25827832

RESUMO

Immunodeficiency dramatically increases susceptibility to cancer as a result of reduced immune surveillance and enhanced opportunities for virus-mediated oncogenesis. Although AIDS-related lymphomas (ARLs) are frequently associated with known oncogenic viruses, many cases contain no known transforming virus. To discover novel transforming viruses, we profiled a set of ARL samples using whole transcriptome sequencing. We determined that Epstein-Barr virus (EBV) was the only virus detected in the tumor samples of this cohort, suggesting that if unidentified pathogens exist in this disease, they are present in <10% of cases or undetectable by our methods. To evaluate the role of EBV in ARL pathogenesis, we analyzed viral gene expression and found highly heterogeneous patterns of viral transcription across samples. We also found significant heterogeneity of viral antigen expression across a large cohort, with many patient samples presenting with restricted type I viral latency, indicating that EBV latency proteins are under increased immunosurveillance in the post-combined antiretroviral therapies era. Furthermore, EBV infection of lymphoma cells in HIV-positive individuals was associated with a distinct host gene expression program. These findings provide insight into the joint host-virus regulatory network of primary ARL tumor samples and expand our understanding of virus-associated oncogenesis. Our findings may also have therapeutic implications, as treatment may be personalized to target specific viral and virus-associated host processes that are only present in a subset of patients.


Assuntos
Transformação Celular Viral , Linfoma Relacionado a AIDS/etiologia , Vírus Oncogênicos , Infecções Tumorais por Vírus/complicações , Análise por Conglomerados , Estudos de Coortes , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/patologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Regulação Viral da Expressão Gênica , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/imunologia , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Linfoma Relacionado a AIDS/patologia , Vírus Oncogênicos/genética , Vírus Oncogênicos/imunologia
3.
Blood ; 122(16): 2837-47, 2013 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-23943653

RESUMO

PU-H71 is a purine-scaffold Hsp90 inhibitor that, in contrast to other Hsp90 inhibitors, displays unique selectivity for binding the fraction of Hsp90 that is preferentially associated with oncogenic client proteins and enriched in tumor cells (teHsp90). This property allows PU-H71 to potently suppress teHsp90 without inducing toxicity in normal cells. We found that lymphoma cells infected by Epstein-Barr virus or Kaposi sarcoma-associated herpes virus (KSHV) are exquisitely sensitive to this compound. Using PU-H71 affinity capture and proteomics, an unbiased approach to reveal oncogenic networks, we identified the teHsp90 interactome in KSHV(+) primary effusion lymphoma cells. Viral and cellular proteins were identified, including many involved in nuclear factor (NF)-κB signaling, apoptosis, and autophagy. KSHV vFLIP is a viral oncoprotein homologous to cFLIPs, with NF-κB-activating and antiapoptotic activities. We show that teHsp90 binds vFLIP but not cFLIPs. Treatment with PU-H71 induced degradation of vFLIP and IKKγ, NF-κB downregulation, apoptosis and autophagy in vitro, and more importantly, tumor responses in mice. Analysis of the interactome revealed apoptosis as a central pathway; therefore, we tested a BCL2 family inhibitor in primary effusion lymphoma cells. We found strong activity and synergy with PU-H71. Our findings demonstrate PU-H71 affinity capture identifies actionable networks that may help design rational combinations of effective therapies.


Assuntos
Benzodioxóis/química , Proteínas de Choque Térmico HSP90/metabolismo , Infecções por Herpesviridae/metabolismo , Neoplasias/metabolismo , Neoplasias/virologia , Purinas/química , Proteínas Virais/metabolismo , Animais , Apoptose , Autofagia , Linhagem Celular Tumoral , Proliferação de Células , Gammaherpesvirinae , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Humanos , Camundongos , NF-kappa B/metabolismo , Transplante de Neoplasias , Proteoma , Proteômica/métodos , Transdução de Sinais
4.
Blood ; 117(18): 4852-4, 2011 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-21406721

RESUMO

A20, a negative regulator of NF-κB, has been implicated as a tumor suppressor gene in multiple types of B-cell lymphoma. AIDS-related lymphomas (ARLs) are high-grade B-cell lymphomas that are frequently associated with EBV infection. We examined a panel of ARLs for A20 alterations. FISH showed A20 deletion in 6 of 33 cases (18%). A20 mutations were found in 3 of 19 cases (16%), including 2 cases with deletions of the comple-mentary allele. Immunohistochemistry showed the absence of A20 protein in 7 of 55 samples (13%). In contrast to reports in Hodgkin lymphoma in which EBV infection and A20 alteration are mutually exclusive, A20 inactivation was observed in both EBV(+) and EBV(-) cases. The EBV latent membrane protein 1, which activates NF-κB, was not expressed in 12 of 13 cases with A20 loss. In ARLs loss of A20 may be an alternative mechanism of NF-κB activation in the absence of latent membrane protein 1 expression.


Assuntos
Infecções por Vírus Epstein-Barr/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Linfoma Relacionado a AIDS/genética , Linfoma Relacionado a AIDS/virologia , Mutação , Proteínas Nucleares/genética , Análise Mutacional de DNA , Proteínas de Ligação a DNA , Infecções por Vírus Epstein-Barr/metabolismo , Deleção de Genes , Inativação Gênica , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Linfoma Relacionado a AIDS/metabolismo , NF-kappa B/metabolismo , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/metabolismo , Proteína 3 Induzida por Fator de Necrose Tumoral alfa , Proteínas da Matriz Viral/metabolismo
5.
Blood ; 118(13): 3559-69, 2011 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-21828137

RESUMO

The phenotype of germinal center (GC) B cells includes the unique ability to tolerate rapid proliferation and the mutagenic actions of activation induced cytosine deaminase (AICDA). Given the importance of epigenetic patterning in determining cellular phenotypes, we examined DNA methylation and the role of DNA methyltransferases in the formation of GCs. DNA methylation profiling revealed a marked shift in DNA methylation patterning in GC B cells versus resting/naive B cells. This shift included significant differential methylation of 235 genes, with concordant inverse changes in gene expression affecting most notably genes of the NFkB and MAP kinase signaling pathways. GC B cells were predominantly hypomethylated compared with naive B cells and AICDA binding sites were highly overrepresented among hypomethylated loci. GC B cells also exhibited greater DNA methylation heterogeneity than naive B cells. Among DNA methyltransferases (DNMTs), only DNMT1 was significantly up-regulated in GC B cells. Dnmt1 hypomorphic mice displayed deficient GC formation and treatment of mice with the DNA methyltransferase inhibitor decitabine resulted in failure to form GCs after immune stimulation. Notably, the GC B cells of Dnmt1 hypomorphic animals showed evidence of increased DNA damage, suggesting dual roles for DNMT1 in DNA methylation and double strand DNA break repair.


Assuntos
Linfócitos B/fisiologia , Diferenciação Celular/genética , DNA (Citosina-5-)-Metiltransferases/fisiologia , Metilação de DNA/fisiologia , Centro Germinativo/imunologia , Animais , Linfócitos B/imunologia , Linfócitos B/metabolismo , Linfócitos B/patologia , Diferenciação Celular/imunologia , Análise por Conglomerados , DNA (Citosina-5-)-Metiltransferase 1 , DNA (Citosina-5-)-Metiltransferases/metabolismo , Epigênese Genética/fisiologia , Perfilação da Expressão Gênica , Centro Germinativo/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Análise em Microsséries , Ovinos , Estudos de Validação como Assunto
6.
Cancer Cell ; 7(5): 445-55, 2005 May.
Artigo em Inglês | MEDLINE | ID: mdl-15894265

RESUMO

Diffuse large B cell lymphomas (DLBCL) derive from germinal center (GC) B cells and display chromosomal alterations deregulating the expression of BCL6, a transcriptional repressor required for GC formation. To investigate the role of BCL6 in DLBCL pathogenesis, we have engineered mice that express BCL6 constitutively in B cells by mimicking a chromosomal translocation found in human DLBCL. These mice display increased GC formation and perturbed post-GC differentiation characterized by a decreased number of post-isotype switch plasma cells. Subsequently, these mice develop a lymphoproliferative syndrome that culminates with the development of lymphomas displaying features typical of human DLBCL. These results define the oncogenic role of BCL6 in the pathogenesis of DLBCL and provide a faithful mouse model of this common disease.


Assuntos
Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Expressão Gênica/genética , Linfoma de Células B/patologia , Linfoma Difuso de Grandes Células B/patologia , Animais , Diferenciação Celular/genética , Aberrações Cromossômicas , Proteínas de Ligação a DNA/metabolismo , Genes de Imunoglobulinas/genética , Centro Germinativo/química , Centro Germinativo/metabolismo , Centro Germinativo/patologia , Hemaglutininas/genética , Humanos , Linfoma de Células B/genética , Linfoma Difuso de Grandes Células B/genética , Linfoma não Hodgkin/genética , Linfoma não Hodgkin/patologia , Transtornos Linfoproliferativos/genética , Transtornos Linfoproliferativos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Camundongos Knockout , Camundongos Transgênicos , Plasmócitos/química , Plasmócitos/metabolismo , Plasmócitos/patologia , Regiões Promotoras Genéticas/genética , Proteínas Proto-Oncogênicas c-bcl-6 , Baço/química , Baço/metabolismo , Baço/patologia , Esplenomegalia/patologia , Análise de Sobrevida , Fatores de Tempo
7.
PLoS One ; 15(1): e0228441, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31999759

RESUMO

A strict cell death control in the intestinal epithelium is indispensable to maintain barrier integrity and homeostasis. In order to achieve a balance between cell proliferation and cell death, a tight regulation of Caspase-8, which is a key player in controlling apoptosis, is required. Caspase-8 activity is regulated by cellular FLIP proteins. These proteins are expressed in different isoforms (cFLIPlong and cFLIPshort) which determine cell death and survival. Interestingly, several viruses encode FLIP proteins, homologous to cFLIPshort, which are described to regulate Caspase-8 and the host cell death machinery. In the current study a mouse model was generated to show the impact of viral FLIP (vFLIP) from Kaposi's Sarcoma-associated Herpesvirus (KSHV)/ Human Herpesvirus-8 (HHV-8) on cell death regulation in the gut. Our results demonstrate that expression of vFlip in intestinal epithelial cells suppressed cFlip expression, but protected mice from lethality, tissue damage and excessive apoptotic cell death induced by genetic cFlip deletion. Finally, our model shows that vFlip expression decreases cFlip mediated Caspase-8 activation in intestinal epithelial cells. In conclusion, our data suggests that viral FLIP neutralizes and compensates for cellular FLIP, efficiently counteracting host cell death induction and facilitating further propagation in the host organism.


Assuntos
Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/metabolismo , Caspase 8/metabolismo , Herpesvirus Humano 8/metabolismo , Mucosa Intestinal/citologia , Animais , Apoptose , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/genética , Proliferação de Células , Deleção de Genes , Herpesvirus Humano 8/genética , Humanos , Mucosa Intestinal/metabolismo , Camundongos , Modelos Animais , Proteínas Virais/genética , Proteínas Virais/metabolismo
8.
Cell Death Dis ; 10(12): 878, 2019 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-31754092

RESUMO

During viral infections viruses express molecules that interfere with the host-cell death machinery and thus inhibit cell death responses. For example the viral FLIP (vFLIP) encoded by Kaposi's sarcoma-associated herpesvirus interacts and inhibits the central cell death effector, Caspase-8. In order to analyze the impact of anti-apoptotic viral proteins, like vFlip, on liver physiology in vivo, mice expressing vFlip constitutively in hepatocytes (vFlipAlbCre+) were generated. Transgenic expression of vFlip caused severe liver tissue injury accompanied by massive hepatocellular necrosis and inflammation that finally culminated in early postnatal death of mice. On a molecular level, hepatocellular death was mediated by RIPK1-MLKL necroptosis driven by an autocrine TNF production. The loss of hepatocytes was accompanied by impaired bile acid production and disruption of the bile duct structure with impact on the liver-gut axis. Notably, embryonic development and tissue homeostasis were unaffected by vFlip expression. In summary our data uncovered that transgenic expression of vFlip can cause severe liver injury in mice, culminating in multiple organ insufficiency and death. These results demonstrate that viral cell death regulatory molecules exhibit different facets of activities beyond the inhibition of cell death that may merit more sophisticated in vitro and in vivo analysis.


Assuntos
Hepatócitos/metabolismo , Hepatócitos/patologia , Falência Hepática/metabolismo , Proteínas Virais/biossíntese , Animais , Morte Celular/fisiologia , Infecções por Herpesviridae/metabolismo , Infecções por Herpesviridae/patologia , Herpesvirus Humano 8/genética , Herpesvirus Humano 8/metabolismo , Humanos , Falência Hepática/genética , Falência Hepática/patologia , Camundongos , Camundongos Transgênicos , Necrose , Transdução de Sinais , Proteínas Virais/genética
9.
Mucosal Immunol ; 11(6): 1621-1629, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30104627

RESUMO

Viruses are present in the intestinal microflora and are currently discussed as a potential causative mechanism for the development of inflammatory bowel disease. A number of viruses, such as Human Herpesvirus-8, express homologs to cellular FLIPs, which are major contributors for the regulation of epithelial cell death. In this study we analyzed the consequences of constitutive expression of HHV8-viral FLIP in intestinal epithelial cells (IECs) in mice. Surprisingly, expression of vFlip disrupts tissue homeostasis and induces severe intestinal inflammation. Moreover vFlipIEC-tg mice showed reduced Paneth cell numbers, associated with excessive necrotic cell death. On a molecular level vFlip expression altered classical and alternative NFκB activation. Blocking of alternative NFκB signaling by deletion of Ikka in vivo largely protected mice from inflammation and Paneth cell loss induced by vFLIP. Collectively, our data provide functional evidence that expression of a single viral protein in IECs can be sufficient to disrupt epithelial homeostasis and to initiate chronic intestinal inflammation.


Assuntos
Infecções por Herpesviridae/metabolismo , Herpesvirus Humano 8/metabolismo , Doenças Inflamatórias Intestinais/virologia , Intestinos/virologia , Proteínas Virais/metabolismo , Animais , Células Cultivadas , Enterócitos/patologia , Enterócitos/virologia , Regulação da Expressão Gênica , Herpesvirus Humano 8/genética , Homeostase , Humanos , Quinase I-kappa B/genética , Doenças Inflamatórias Intestinais/patologia , Intestinos/patologia , Camundongos , Camundongos Knockout , Camundongos Transgênicos , NF-kappa B/genética , NF-kappa B/metabolismo , Necrose
10.
AIDS ; 16(1): 63-73, 2002 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-11741164

RESUMO

OBJECTIVE: Patients infected with HIV-1 are at high risk of developing Epstein-Barr virus (EBV)-associated lymphoproliferative disorders. This study evaluated the impact of highly active antiretroviral therapy (HAART) on EBV infection. METHODS: To measure EBV content in peripheral blood lymphocytes (PBL) and in plasma, we set up a quantitative analysis using the real-time PCR. EBV latent membrane protein 1 (LMP1) expression was determined by reverse transcriptase-PCR. RESULTS: EBV levels were determined in 33 HIV-1- and EBV-coinfected patients at the start of HAART, and during therapy. At baseline, EBV content in PBL samples ranged from 8 to 14 532 copies/microg DNA. EBV levels transiently increased in nine out of 17 patients in whom HIV-1 plasmaviraemia declined to undetectable levels (virological response) and CD4 cell counts increased (immunological response), while they remained fairly stable or decreased in the other eight virological and immunological responders, and in seven patients who showed a virological response only. Of interest, a significant increase in EBV load was observed in five out of nine patients who showed an increase in CD4 cell counts but lack of HIV-1 suppression during HAART. This EBV increase was accompanied by the detection of both LMP1 transcripts in PBL and EBV DNA in plasma, and was paralleled by an increase in immunoglobulin levels, a marker of B-cell stimulation. CONCLUSIONS: These findings suggest that peripheral immune reconstitution during HAART without a reduction in HIV-1 replication may increase B-cell stimulation and the number of EBV-infected B cells.


Assuntos
Terapia Antirretroviral de Alta Atividade , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Herpesvirus Humano 4/fisiologia , Carga Viral , Adulto , Idoso , Anticorpos Antivirais/sangue , Contagem de Linfócito CD4 , DNA Viral/sangue , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Infecções por Vírus Epstein-Barr/virologia , Feminino , Infecções por HIV/imunologia , HIV-1/isolamento & purificação , HIV-1/fisiologia , Herpesvirus Humano 4/isolamento & purificação , Humanos , Leucócitos Mononucleares/virologia , Masculino , Pessoa de Meia-Idade , Proteínas da Matriz Viral/genética , Proteínas da Matriz Viral/metabolismo
11.
J Clin Invest ; 121(3): 1141-53, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21339646

RESUMO

Kaposi sarcoma herpesvirus (KSHV) is specifically associated with Kaposi sarcoma (KS) and 2 B cell lymphoproliferative diseases, namely primary effusion lymphoma (PEL) and multicentric Castleman disease (MCD). KS, PEL, and MCD are largely incurable and poorly understood diseases most common in HIV-infected individuals. Here, we have revealed the role of viral FLICE-inhibitory protein (vFLIP) in the initiation of PEL and MCD by specifically expressing vFLIP at different stages of B cell differentiation in vivo. Mice showed MCD-like abnormalities and immunological defects including lack of germinal centers (GCs), impaired Ig class switching, and affinity maturation. In addition, they showed increased numbers of cells expressing cytoplasmic IgM-λ, a thus far enigmatic feature of the KSHV-infected cells in MCD. B cell-derived tumors arose at high incidence and displayed Ig gene rearrangement with downregulated expression of B cell-associated antigens, which are features of PEL. Interestingly, these tumors exhibited characteristics of transdifferentiation and acquired expression of histiocytic/dendritic cell markers. These results define immunological functions for vFLIP in vivo and reveal what we believe to be a novel viral-mediated tumorigenic mechanism involving B cell reprogramming. Additionally, the robust recapitulation of KSHV-associated diseases in mice provides a model to test inhibitors of vFLIP as potential anticancer agents.


Assuntos
Linfócitos B/citologia , Regulação Neoplásica da Expressão Gênica , Herpesvirus Humano 8/metabolismo , Sarcoma de Kaposi/virologia , Proteínas Virais/genética , Animais , Antineoplásicos/farmacologia , Diferenciação Celular , Transdiferenciação Celular , Intervalo Livre de Doença , Regulação para Baixo , Humanos , Switching de Imunoglobulina , Camundongos , Neoplasias/metabolismo , Fosforilação , Proteínas Virais/metabolismo
12.
Trends Microbiol ; 18(6): 248-57, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20452220

RESUMO

The nuclear factor (NF)-kappaB signaling pathway is pivotal for immune system function. Not surprisingly, pathogenic microorganisms have developed strategies to subvert it. Two examples are Epstein-Barr virus (EBV) and Kaposi sarcoma herpesvirus (KSHV), oncogenic gammaherpesviruses that establish a lifelong latent infection in their human hosts. The modulation of NF-kappaB signaling by EBV and KSHV is not only important for viral infection, but also contributes to the development of malignant neoplasia. This review explores the current knowledge of NF-kappaB modulation by EBV and KSHV, focusing on connections between viral biology and human carcinogenesis.


Assuntos
Transformação Celular Neoplásica , Infecções por Herpesviridae/virologia , Herpesvirus Humano 4/metabolismo , Herpesvirus Humano 8/metabolismo , NF-kappa B/metabolismo , Neoplasias/virologia , Transdução de Sinais , Animais , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/metabolismo , Infecções por Vírus Epstein-Barr/virologia , Regulação Viral da Expressão Gênica , Infecções por Herpesviridae/imunologia , Infecções por Herpesviridae/metabolismo , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/patogenicidade , Herpesvirus Humano 8/genética , Herpesvirus Humano 8/patogenicidade , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Camundongos , Neoplasias/imunologia , Neoplasias/metabolismo
13.
Exp Cell Res ; 295(2): 539-48, 2004 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-15093750

RESUMO

Patients infected with human immunodeficiency virus type 1 (HIV-1) develop a spectrum of B cell lymphoproliferative disorders ranging from polyclonal B cell activation to B cell lymphomas. While a direct role of Epstein-Barr virus (EBV) is well recognized for most of these lesions, recent findings have suggested that transactivator HIV-1 Tat protein might be involved in the pathogenesis of B cell lymphomas. Tat-expressing EBV-positive B cells were generated by transduction with a retroviral Tat-encoding vector. B(Tat+) cells expressed lower levels of anti-apoptotic protein Bcl-2 than parental and control B(Tat-) cells, generated by transduction with an empty retroviral vector, and were more prone to apoptosis upon serum withdrawal, as assessed by analysis of annexin V-stained cells and cleavage of poly-ADP-ribose-polymerase by caspase 3. Nevertheless, in serum starvation, B(Tat-) cells mainly exhibited the Rb hypo-phosphorylated form, underwent cell cycle arrest, and grew in single cell suspension, while B(Tat+) cells displayed the Rb hyper-phoshorylated form, progressed throughout the cell cycle, and retained the ability to grow in small clumps. Finding that B(Tat+) cells maintained proliferative capacity upon serum withdrawal suggests that cells expressing Tat have growth advantages among the EBV-driven cell proliferations and may originate B cell clones with more oncogenic potential.


Assuntos
Apoptose , Linfócitos B/virologia , Ciclo Celular , Produtos do Gene tat/metabolismo , HIV-1/fisiologia , Herpesvirus Humano 4/fisiologia , Anexina A5/metabolismo , Linfócitos B/citologia , Linfócitos B/metabolismo , Caspases/metabolismo , Divisão Celular , Linhagem Celular , Linhagem Celular Transformada , Transformação Celular Viral , Meios de Cultura Livres de Soro , Regulação Viral da Expressão Gênica , Produtos do Gene tat/genética , Humanos , Fosforilação , Retinoblastoma/genética , Retinoblastoma/metabolismo , Retroviridae/genética , Proteínas Virais/análise , Proteínas Virais/metabolismo , Produtos do Gene tat do Vírus da Imunodeficiência Humana
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