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1.
Virologie (Montrouge) ; 12(1): 39-52, 2008 Feb 01.
Artigo em Francês | MEDLINE | ID: mdl-36131433

RESUMO

Discovered in 1957 for their antiviral properties, interferons (IFNs) are a growing cytokine family with diverse biological activities including antitumor and immunoregulatory activities. IFN are classified in three types I, II and III. They bind to different specific cell receptors and induce via the Jak/Stat pathway the expression of more than 300 genes, the products of which are believed to mediate their biological effects. Several proteins have been implicated in resistance to viral infection in IFN-treated cells, i.e. the dsRNAdependent protein kinase PKR, the 2'5' oligoadenylate synthetase/RNaseL and Mx proteins. However, it was demonstrated that cells from triple knockout mice lacking PKR, RNase L and Mx are still sensitive to the IFN-induced antiviral state, indicating that other pathways exist. One of these pathways implicates promyelocytic leukemia (PML) protein. This article reviews the potential antiviral activities of the different IFN-induced mediators focusing onPMLpathway and how viruses from different families overcome this defence.

2.
Cell Mol Biol (Noisy-le-grand) ; 52(1): 9-15, 2006 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-16914093

RESUMO

Interferons (IFNs) and arsenic trioxide (As2O3) are known inhibitors of cell proliferation and have been used in the treatment of certain forms of malignancy. IFNgamma treatment of cells leads to tyrosine phosphorylation of STAT1 followed by dimerization that accumulates in the nucleus. This is followed by DNA binding, activation of target gene transcription, dephosphorylation, and return to the cytoplasm. We have shown earlier that IFNgamma and As2O3 act synergistically in acute promyelocytic leukemia cells to upregulate IRF-1 expression and to induce apoptosis. Here, we show that in the human fibrosarcoma cell line 2fTGH, As2O3 prolongs IFNgamma-induced STAT1 phosphorylation resulting in persistent binding of STAT1 to GAS motif leading to an increase in IRF-1 expression which correlated with both higher anti-proliferative effect and increased apoptosis. These biological responses induced by IFNgamma alone or in combination with As2O3 were abolished when IRF-1 expression was down-regulated by RNA interference, thus demonstrating the key role of IRF-1.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Arsênio/farmacologia , Fator Regulador 1 de Interferon/fisiologia , Interferon gama/farmacologia , Motivos de Aminoácidos , Proteínas de Ciclo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Proteínas Ligadas por GPI , Expressão Gênica/efeitos dos fármacos , Inibidores do Crescimento/farmacologia , Humanos , Fator Regulador 1 de Interferon/metabolismo , Proteínas de Membrana/metabolismo , Modelos Biológicos , Fosforilação/efeitos dos fármacos , Ligação Proteica/efeitos dos fármacos , Fator de Transcrição STAT1/metabolismo , Células Tumorais Cultivadas
4.
Oncogene ; 20(49): 7274-86, 2001 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-11704856

RESUMO

Interferons (IFNs) are a family of secreted proteins with antiviral, antiproliferative and immunomodulatory activities. The different biological actions of IFN are believed to be mediated by the products of specifically induced cellular genes in the target cells. The promyelocytic leukaemia (PML) protein localizes both in the nucleoplasm and in matrix-associated multi-protein complexes known as nuclear bodies (NBs). PML is essential for the proper formation and the integrity of the NBs. Modification of PML by the Small Ubiquitin MOdifier (SUMO) was shown to be required for its localization in NBs. The number and the intensity of PML NBs increase in response to interferon (IFN). Inactivation of the IFN-induced PML gene by its fusion to retinoic acid receptor alpha alters the normal localization of PML from the punctuate nuclear patterns of NBs to micro-dispersed tiny dots and results in uncontrolled growth in Acute Promyelocytic Leukaemia. The NBs-associated proteins, PML, Sp100, Sp140, Sp110, ISG20 and PA28 are induced by IFN suggesting that nuclear bodies could play a role in IFN response. Although the function of PML NBs is still unclear, some results indicate that they may represent preferential targets for viral infections and that PML could play a role in the mechanism of the antiviral action of IFNs. Viruses, which require the cellular machinery for their replication, have evolved different ways to counteract the action of IFN by inhibiting IFN signalling, by blocking the activities of specific antiviral mediators or by altering PML expression and/or localization on nuclear bodies.


Assuntos
Estruturas do Núcleo Celular/metabolismo , Infecções por Vírus de DNA/metabolismo , Proteínas de Ligação ao GTP , Interferons/metabolismo , Proteínas de Neoplasias/metabolismo , Organelas/metabolismo , Infecções por Vírus de RNA/metabolismo , Fatores de Transcrição/metabolismo , Animais , Estruturas do Núcleo Celular/efeitos dos fármacos , Enzimas/metabolismo , Expressão Gênica/efeitos dos fármacos , Humanos , Interferons/farmacologia , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/metabolismo , Proteínas de Resistência a Myxovirus , Proteínas Nucleares/metabolismo , Organelas/efeitos dos fármacos , Proteína da Leucemia Promielocítica , Proteínas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Supressoras de Tumor
5.
EMBO J ; 20(13): 3495-505, 2001 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-11432836

RESUMO

The promyelocytic leukaemia (PML) protein localizes in the nucleus both in the nucleoplasm and in matrix-associated multiprotein complexes known as nuclear bodies (NBs). The number and the intensity of PML NBs increase in response to interferon (IFN). Overexpression of PML affects the replication of vesicular stomatitis virus and influenza virus. However, PML has a less powerful antiviral activity against these viruses than the IFN mediator MxA. Here, we show that overexpression of PML, but not that of Mx1 or MxA, leads to a drastic decrease of a complex retrovirus, the human foamy virus (HFV), gene expression. PML represses HFV transcription by complexing the HFV transactivator, Tas, preventing its direct binding to viral DNA. This physical interaction requires the N-terminal region of Tas and the RING finger of PML, but does not necessitate PML localization in NBs. Finally, we show that IFN treatment inhibits HFV replication in wild-type but not in PML-/- cells. These findings point to a role for PML in transcriptional repression and suggest that PML could play a key role in mediating an IFN-induced antiviral state against a complex retrovirus.


Assuntos
Antivirais/metabolismo , Proteínas de Ligação ao GTP , Interferon-alfa/farmacologia , Proteínas de Neoplasias/metabolismo , Proteínas/metabolismo , Spumavirus/fisiologia , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Animais , Astrocitoma , Células CHO , Cricetinae , DNA Viral/genética , Fibroblastos/fisiologia , Fibroblastos/virologia , Glioblastoma , Humanos , Células L , Camundongos , Camundongos Knockout , Proteínas de Resistência a Myxovirus , Proteínas de Neoplasias/genética , Proteínas Nucleares/metabolismo , Proteína da Leucemia Promielocítica , RNA Mensageiro/genética , RNA Viral/genética , DNA Polimerase Dirigida por RNA/metabolismo , Proteínas Recombinantes/metabolismo , Spumavirus/efeitos dos fármacos , Spumavirus/genética , Fatores de Transcrição/genética , Transfecção , Células Tumorais Cultivadas , Proteínas Supressoras de Tumor , Replicação Viral/efeitos dos fármacos
6.
Oncogene ; 19(44): 5041-53, 2000 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-11042692

RESUMO

Type I Interferon (IFN) and all-trans retinoic acid (RA) inhibit cell proliferation of squamous carcinoma cell lines (SCC). Examinations of growth-affected cell populations show that SCC lines ME-180 and SiHa treated with IFN-beta undergo a specific slower progression through the S phase that seems to trigger cellular death. In combination treatment RA potentiates IFN-beta effect in SCC ME-180 but not in SiHa cell line, partially resistant to RA antiproliferative action. RA added as single agent affects cell proliferation differently by inducing a slight G1 accumulation. The IFN-beta-induced S phase lengthening parallels the increased expression of PML, a nuclear phosphoprotein specifically up-regulated at transcriptional level by IFN, whose overexpression induces cell growth inhibition and tumor suppression. We report that PML up-regulation may account for the alteration of cell cycle progression induced by IFN-beta in SCC by infecting cells with PML-PINCO recombinant retrovirus carrying the PML-3 cDNA under the control of the 5' LTR. In fact PML overexpression reproduces the IFN-beta-induced S phase lengthening. These findings provide important insight into the mechanism of tumor suppressing function of PML and could allow PML to be included in the pathways responsible for IFN-induced cell growth suppression.


Assuntos
Antineoplásicos/farmacologia , Carcinoma de Células Escamosas/patologia , Interferon Tipo I/farmacologia , Proteínas de Neoplasias/biossíntese , Proteínas Nucleares , Fase S/efeitos dos fármacos , Fatores de Transcrição/biossíntese , Neoplasias do Colo do Útero/patologia , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Divisão Celular/efeitos dos fármacos , DNA de Neoplasias/biossíntese , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inibidores do Crescimento/administração & dosagem , Inibidores do Crescimento/farmacologia , Humanos , Interferon Tipo I/administração & dosagem , Proteínas de Neoplasias/genética , Proteína da Leucemia Promielocítica , Isoformas de Proteínas/biossíntese , Isoformas de Proteínas/genética , Proteínas Recombinantes , Fatores de Transcrição/genética , Tretinoína/administração & dosagem , Tretinoína/farmacologia , Células Tumorais Cultivadas , Proteínas Supressoras de Tumor , Regulação para Cima/efeitos dos fármacos , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/metabolismo
7.
Leukemia ; 14(4): 716-21, 2000 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-10764160

RESUMO

The combination of the anti-viral agents, zidovudine (AZT) and interferon-alpha (IFN), is a potent treatment of HTLV-I-associated adult T cell leukemia/lymphoma (ATL). In this study we investigate the possible mechanism of action of this combination by examining several cellular parameters including cell proliferation, cell cycle distribution and apoptosis. The ATL-derived T cell lines HuT-102 and MT-2 served as models. HTLV-I negative T cell lines (CEM and Jurkat) were used as controls. No significant modification of cell growth was observed except at suprapharmacological doses of AZT and IFN. Moreover, these effects were less pronounced in HTLV-I-infected cell lines compared to control cell lines. AZT and IFN treatment did not induce any significant modification of the expression of bcl-2 and p53. Interestingly no in vitro cytotoxic effect of AZT/IFN combination was observed on fresh leukemic cells derived from an acute ATL patient at diagnosis despite achievement of in vivo complete remission using the same therapy. These results suggest that the therapeutic effect of AZT and IFN is not through a direct cytotoxic effect of these drugs on the leukemic cells.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Fatores Imunológicos/farmacologia , Interferon-alfa/farmacologia , Leucemia-Linfoma de Células T do Adulto/tratamento farmacológico , Células-Tronco Neoplásicas/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Zidovudina/farmacologia , Idoso , Antimetabólitos Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Biomarcadores Tumorais/análise , Sobrevivência Celular/efeitos dos fármacos , Terapia Combinada , DNA de Neoplasias/análise , Sinergismo Farmacológico , Feminino , Vírus Linfotrópico T Tipo 1 Humano/isolamento & purificação , Humanos , Fatores Imunológicos/uso terapêutico , Interferon-alfa/uso terapêutico , Células Jurkat/efeitos dos fármacos , Leucemia-Linfoma de Células T do Adulto/patologia , Indução de Remissão , Células Tumorais Cultivadas/efeitos dos fármacos , Zidovudina/uso terapêutico
8.
Leukemia ; 13(8): 1167-74, 1999 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-10450744

RESUMO

Retinoic acid (RA) and interferon (IFN) potentiate each other to induce biological responses. Their combination has shown synergistic differentiating, antiproliferative and antiviral activities in various cell lines including those derived from the acute promyelocytic leukemia (APL). IFNs have demonstrated broad applications in cancer, as well as in virologic diseases. RA has variable effectiveness in therapy. Its real success is in APL where it provides the first example of a differentiation therapy. However, complete clinical remission with RA alone is always transient as RA resistance develops in the treated patients as well as in vitro. In various cell lines, including those derived from APL, RA induces directly the expression of two transcription factors, Stat1 and IRF-1 which play central roles in the IFN signal transduction. In addition, RA induces IFN-alpha synthesis and enhances the IFN-induced Stat activation. Here, we review the molecular mechanisms by which RA and IFNs can cooperate in inducing differentiation, inhibition of cell growth or viral replication focusing on recent results derived from normal and RA-resistant APL cells.


Assuntos
Antineoplásicos/farmacologia , Interferons/farmacologia , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/metabolismo , Receptores de Interferon/metabolismo , Receptores do Ácido Retinoico/metabolismo , Transdução de Sinais , Tretinoína/farmacologia , Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Humanos , Interferons/uso terapêutico , Receptor Cross-Talk , Tretinoína/uso terapêutico
9.
Oncogene ; 18(27): 3944-53, 1999 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-10435617

RESUMO

In the t(15;17) acute promyelocytic leukaemia (APL), all trans-retinoic (RA) treatment induces maturation leading to clinically complete but not durable remission, as RA resistance develops in the treated patients as well as in vitro. RA and interferons (IFNs) are known inhibitors of proliferation in various cells including those from APL. In this report, we show that they can act cooperatively to inhibit growth and to induce differentiation of NB4 cells but not of two RA-resistant NB4 derived cell lines, NB4-R1 and NB4-R2. However, the resistant cell lines respond to IFN. In NB4 cells, RA increases the expression of Stat1, p48 and IRF-1, three transcription factors playing a central role in the IFN response and induces the synthesis and the secretion of IFN alpha. RA-induced IFN alpha seems to play a role in inhibition of NB4 cell growth but not in their differentiation. In the resistant cells, NB4-R1 and NB4-R2, both the induction of IFN and the increase of Statl and p48 expression by RA are completely blocked. In contrast, IRF-1 mRNA and protein expressions are induced in the three cell lines. This suggests that increase of IRF-1 expression is not sufficient for IFN induction. Our results identify some defects linked to RA-resistance in APL and support the hypothesis that RA-induced Stat1 expression and IFN secretion may be one of the mechanisms mediating growth inhibition by RA.


Assuntos
Proteínas de Ligação a DNA/biossíntese , Interferon-alfa/biossíntese , Leucemia Promielocítica Aguda/metabolismo , Transativadores/biossíntese , Fatores de Transcrição/biossíntese , Tretinoína/farmacologia , Diferenciação Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Proteínas de Ligação a DNA/metabolismo , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Inibidores do Crescimento/fisiologia , Humanos , Fator Regulador 1 de Interferon , Fator Regulador 3 de Interferon , Fator Gênico 3 Estimulado por Interferon , Fator Gênico 3 Estimulado por Interferon, Subunidade gama , Interferon-alfa/farmacologia , Interferon-alfa/fisiologia , Leucemia Promielocítica Aguda/patologia , Fosfoproteínas/biossíntese , Fosfoproteínas/metabolismo , Fosforilação , Fator de Transcrição STAT1 , Transdução de Sinais/efeitos dos fármacos , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Células Tumorais Cultivadas
10.
Oncogene ; 18(4): 935-41, 1999 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-10023669

RESUMO

The PML protein is associated to nuclear bodies (NBs) whose functions are as yet unknown. PML and two other NBs-associated proteins, Sp100 And ISG20 are directly induced by interferons (IFN). PML and Sp100 proteins are covalently linked to SUMO-1, and ubiquitin-like peptide. PML NBs are disorganized in acute promyelocytic leukemia and during several DNA virus infections. In particular, the HSV-1 ICP0 protein is known to delocalize PML from NBs. Thus, NBs could play an important role in oncogenesis, IFN response and viral infections. Here, we show that HSV-1 induced PML protein degradation without altering its mRNA level. This degradation was time- and multiplicity of infection-dependent. Sp100 protein was also degraded, while another SUMO-1 conjugated protein, RanGAP1 and the IFN-induced protein kinase PKR were not. The proteasome inhibitor MG132 abrogated the HSV-1-induced PML and Sp100 degradation and partially restored their NB-localization. HSV-1 induced PML and Sp100 degradation constitutes a new example of viral inactivation of IFN target gene products.


Assuntos
Antígenos Nucleares , Autoantígenos/metabolismo , Proteínas Ativadoras de GTPase , Herpes Simples/metabolismo , Herpesvirus Humano 1 , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Fatores de Transcrição/metabolismo , Autoantígenos/química , Proteínas de Transporte/metabolismo , Inibidores de Cisteína Proteinase/farmacologia , Humanos , Interferons/farmacologia , Leupeptinas/farmacologia , Peso Molecular , Proteínas de Neoplasias/química , Proteínas Nucleares/química , Proteína da Leucemia Promielocítica , Proteínas Quinases/metabolismo , RNA Mensageiro/metabolismo , Proteína SUMO-1 , Fatores de Tempo , Fatores de Transcrição/química , Células Tumorais Cultivadas , Proteínas Supressoras de Tumor , Ubiquitinas/metabolismo
11.
Biol Cell ; 91(8): 617-28, 1999 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-10629941

RESUMO

The present study has documented changes in the in situ distribution of viral DNA and capsid proteins in 293 cells infected with fiber gene-deleted adenoviruses. It shows that infection results in the intense production of progeny viruses which appear morphologically intact although they are devoid of fiber-coding sequence in their genome and hence of fiber protein in their capsid. The data confirm, therefore, that fiber protein is not essential for the assembly of progeny viruses. The main contribution of our observations concerns specific intranuclear structures induced by infection with either wild-type or fiber gene-deleted viruses. These clear amorphous inclusions contain two cellular proteins, PML and Sp100, which in non-infected cells co-localize to a special type of nuclear bodies. PML and Sp100 nuclear bodies appear to directly modulate or to be altered in a wide variety of situations including viral infections, cell death and transformation. In cells infected with fiber gene-deleted viruses, the clear amorphous inclusions now accumulate non-used hexon and penton base proteins, whereas the absence of fiber protein prevents the assembly of capsid proteins in crystallin arrays. Taken together, the data suggest that the clear amorphous inclusions may correspond to storage sites of structural and regulatory proteins. Consequently, these virus-induced structures may promote the productive cycle of adenoviruses by regulating the amount of over-produced viral proteins and the shutoff of the host cell metabolism.


Assuntos
Infecções por Adenoviridae/genética , Adenoviridae/genética , Antígenos Nucleares , Autoantígenos/análise , Proteínas do Capsídeo , Capsídeo/metabolismo , Deleção de Genes , Proteínas de Neoplasias/análise , Proteínas Nucleares/análise , Fatores de Transcrição/análise , Adenoviridae/ultraestrutura , Núcleo Celular/química , Núcleo Celular/ultraestrutura , Núcleo Celular/virologia , Células Cultivadas , DNA Viral/análise , DNA Viral/genética , Imuno-Histoquímica , Hibridização In Situ , Corpos de Inclusão/química , Corpos de Inclusão/ultraestrutura , Microscopia Eletrônica , Proteínas Supressoras de Tumor
12.
Bull Cancer ; 85(4): 313-8, 1998 Apr.
Artigo em Francês | MEDLINE | ID: mdl-9752294

RESUMO

Retinoic acid (RA) and interferons (IFN) are negative regulators of cell proliferation. A number of clinical trials were thus carried out in cancer therapy with RA and/or IFN. In vitro and in vivo, their combination leads to a more potent cell growth inhibition. Moreover, RA and IFN act cooperatively to increase the expression of many IFN-stimulated genes, leading also to a higher cell differentiation and inhibition of viral replication. However, the molecular mechanisms by which RA and IFN potentiate each other are not fully understood. The cooperative effects by RA and IFN are mediated through multiple pathways. RA causes the induction and secretion of IFN alpha. RA also stimulates the IFN regulatory factor gene expression (IRF1 and p48). Additional mechanisms could be involved as RA increases the level of signal transducing activators of transcription (Stat) proteins, and thus enhances the IFN-induced Stat activation.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Interferons/uso terapêutico , Tretinoína/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/metabolismo , Interações Medicamentosas , Humanos , Interferon-alfa/metabolismo , Interferon beta/metabolismo , Interferons/administração & dosagem , Interferons/classificação , Interferons/metabolismo , Fosforilação , Transdução de Sinais , Transativadores/metabolismo , Tretinoína/administração & dosagem , Tretinoína/metabolismo
13.
Blood ; 91(11): 4300-10, 1998 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-9596679

RESUMO

In the acute promyelocytic leukemia (APL) cell line NB4, as well as in APL patients' cells, arsenic trioxide (As2O3) leads to incomplete cell maturation, induction of apoptosis, as well as to the degradation of the oncogenic PML/RARalpha fusion protein. We have isolated an arsenic-resistant NB4 subline (NB4-AsR), which fails to undergo apoptosis, but maintains the partial differentiation response to this drug. When grown in the presence of As2O3, NB4-AsR cells degrade PML/RARalpha, slightly differentiate, and become more sensitive to serum deprivation-induced apoptosis. Similarly, in RA-resistant NB4-R1 cells, RA induced a significant PML/RARalpha degradation and yet failed to induce cell maturation. Thus, As2O3- or retinoic acid (RA)-induced PML/RARalpha degradation may be a prerequisite, but is not sufficient for the full differentiative/apoptotic response to these drugs. Strikingly, RA-triggered differentiation and apoptosis were greatly accelerated in As2O3-treated NB4-AsR cells. The synergism between these two agents in this setting could provide an experimental basis for combined or sequential RA/As2O3 therapies.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Arsenicais/farmacologia , Óxidos/farmacologia , Tretinoína/farmacologia , Trióxido de Arsênio , Diferenciação Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Humanos , Leucemia Promielocítica Aguda/patologia , Microscopia Confocal , Células Tumorais Cultivadas
14.
J Virol ; 72(2): 1043-51, 1998 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-9444998

RESUMO

The interferon (IFN)-induced promyelocytic leukemia (PML) protein is specifically associated with nuclear bodies (NBs) whose functions are yet unknown. Two of the NB-associated proteins, PML and Sp100, are induced by IFN. Here we show that overexpression of PML and not Sp100 induces resistance to infections by vesicular stomatitis virus (VSV) (a rhabdovirus) and influenza A virus (an orthomyxovirus) but not by encephalomyocarditis virus (a picornavirus). Inhibition of viral multiplication was dependent on both the level of PML expression and the multiplicity of infection and reached 100-fold. PML was shown to interfere with VSV mRNA and protein synthesis. Compared to the IFN mediator MxA protein, PML had less powerful antiviral activity. While nuclear body localization of PML did not seem to be required for the antiviral effect, deletion of the PML coiled-coil domain completely abolished it. Taken together, these results suggest that PML can contribute to the antiviral state induced in IFN-treated cells.


Assuntos
Antígenos Nucleares , Vírus da Influenza A , Influenza Humana/metabolismo , Interferons/farmacologia , Proteínas de Neoplasias , Infecções por Rhabdoviridae/metabolismo , Fatores de Transcrição/metabolismo , Vírus da Estomatite Vesicular Indiana , Animais , Autoantígenos/metabolismo , Células CHO , Cricetinae , Suscetibilidade a Doenças , Humanos , Proteínas Nucleares/metabolismo , Proteína da Leucemia Promielocítica , Células Tumorais Cultivadas , Proteínas Supressoras de Tumor
15.
Oncogene ; 15(19): 2349-59, 1997 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-9393879

RESUMO

Retinoic acid (RA) and interferons (IFNs) are negative regulators of cell proliferation. In vitro and in vivo, their combination leads to a more potent growth inhibition. However, the molecular mechanisms by which RA and IFNs potentiate each other are not fully understood. As some IFN-induced gene products regulate cell growth and/or antiviral activity, we analysed the effects of RA on their expressions. RA increases the level of 2'5'oligoadenylate synthetase, p68 kinase, the promyelocytic leukemia protein (PML) and Sp100 in both HL-60 and WISH cells. Moreover, RA and IFN act cooperatively to increase the expression of these proteins. RA also inhibits vesicular stomatitis virus replication and induces a higher antiviral state and growth inhibition when combined with IFN. RA stimulates the IFN regulatory factor 1 (IRF-1) gene expression directly through the GAS motif and causes the induction and secretion of IFNalpha. Additional mechanisms could be involved as RA increases the level of signal transducing activators of transcription (STAT) proteins, and enhances the IFN-induced STAT activation, suggesting that cooperative effects by RA and IFN are mediated through multiple pathways.


Assuntos
Antígenos Nucleares , Interferon-alfa/farmacologia , Tretinoína/farmacologia , 2',5'-Oligoadenilato Sintetase/metabolismo , Autoantígenos/metabolismo , Divisão Celular/efeitos dos fármacos , Linhagem Celular , Sinergismo Farmacológico , Células HL-60 , Células HeLa , Humanos , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Transdução de Sinais , Vírus da Estomatite Vesicular Indiana/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
16.
Proc Natl Acad Sci U S A ; 94(19): 10255-60, 1997 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-9294197

RESUMO

In acute promyelocytic leukemia (APL), the typical t(15;17) and the rare t(11;17) translocations express, respectively, the PML/RARalpha and PLZF/RARalpha fusion proteins (where RARalpha is retinoic acid receptor alpha). Herein, we demonstrate that the PLZF and PML proteins interact with each other and colocalize onto nuclear bodies (NBs). Furthermore, induction of PML expression by interferons leads to a recruitment of PLZF onto NBs without increase in the levels of the PLZF protein. PML/RARalpha and PLZF/RARalpha localize to the same microspeckled nuclear domains that appear to be common targets for the two fusion proteins in APL. Although PLZF/RARalpha does not affect the localization of PML, PML/RARalpha delocalizes the endogenous PLZF protein in t(15;17)-positive NB4 cells, pointing to a hierarchy in the nuclear targeting of these proteins. Thus, our results unify the molecular pathogenesis of APL with at least two different RARalpha gene translocations and stress the importance of alterations of PLZF and RARalpha nuclear localizations in this disease.


Assuntos
Núcleo Celular/metabolismo , Proteínas de Ligação a DNA/metabolismo , Leucemia Promielocítica Aguda/metabolismo , Proteínas de Neoplasias , Proteínas Nucleares , Receptores do Ácido Retinoico/metabolismo , Fatores de Transcrição/metabolismo , Animais , Células COS , Dimerização , Ligação Proteica , Proteínas Recombinantes de Fusão/metabolismo , Receptor alfa de Ácido Retinoico , Proteínas Supressoras de Tumor
17.
Proc Natl Acad Sci U S A ; 94(8): 3978-83, 1997 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-9108090

RESUMO

Acute promyelocytic leukemia (APL) is associated with the t(15;17) translocation, which generates a PML/RAR alpha fusion protein between PML, a growth suppressor localized on nuclear matrix-associated bodies, and RAR alpha, a nuclear receptor for retinoic acid (RA). PML/RAR alpha was proposed to block myeloid differentiation through inhibition of nuclear receptor response, as does a dominant negative RAR alpha mutant. In addition, in APL cells, PML/RAR alpha displaces PML and other nuclear body (NB) antigens onto nuclear microspeckles, likely resulting in the loss of PML and/or NB functions. RA leads to clinical remissions through induction of terminal differentiation, for which the respective contributions of RAR alpha (or PML/RAR alpha) activation, PML/RAR alpha degradation, and restoration of NB antigens localization are poorly determined. Arsenic trioxide also leads to remissions in APL patients, presumably through induction of apoptosis. We demonstrate that in non-APL cells, arsenic recruits the nucleoplasmic form of several NB antigens onto NB, but induces the degradation of PML only, identifying a powerful tool to approach NB function. In APL cells, arsenic targets PML and PML/RAR alpha onto NB and induces their degradation. Thus, RA and arsenic target RAR alpha and PML, respectively, but both induce the degradation of the PML/RAR alpha fusion protein, which should contribute to their therapeutic effects. The difference in the cellular events triggered by these two agents likely stems from RA-induced transcriptional activation and arsenic effects on NB proteins.


Assuntos
Arsênio/farmacologia , Núcleo Celular/metabolismo , Leucemia Promielocítica Aguda/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas de Fusão Oncogênica/metabolismo , Apoptose/efeitos dos fármacos , Transporte Biológico/efeitos dos fármacos , Humanos , Leucemia Promielocítica Aguda/patologia , Leucemia Promielocítica Aguda/terapia
18.
Exp Cell Res ; 229(2): 253-60, 1996 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-8986606

RESUMO

Acute promyelocytic leukemia (APL) is specifically associated to a t(15; 17) translocation which fuses a gene encoding a nuclear receptor for retinoic acid, RARalpha, to a previously unknown gene PML. The PML protein is localized in the nucleus on a specific domain of unknown function (PML nuclear bodies, NB) previously detected with autoimmune sera from patients with primary biliary cirrhosis (PBC). These bodies are nuclear matrix-associated and all of their identified components (PML, Sp100, and NDP52) are sharply upregulated by interferons. We show that autoantibodies against both PML and Sp100 are usually associated in sera with multiple nuclear dot anti-nuclear antibodies and demonstrate that PML is an autoantigen, not only in PBC, but also in other autoimmune diseases. In APL, the PML/RARalpha fusion interferes with both the retinoic acid (RA) response and PML localization on nuclear bodies, but the respective contribution of each defect to leukemogenesis is unclear. RA induces the terminal differentiation of APL blasts, yielding to complete remissions, and corrects the localization of NB antigens. Arsenic trioxide (As2O3) also induces remissions in APL, seemingly through induction of apoptosis. We show that in APL, As2O3 leads to the rapid reformation of PML bodies. Thus, both agents correct the defect in NB antigen localization, stressing the role of nuclear bodies in the pathogenesis of APL.


Assuntos
Doenças Autoimunes/genética , Leucemia Promielocítica Aguda/genética , Proteínas de Neoplasias/genética , Proteínas Nucleares , Proteínas de Fusão Oncogênica/genética , Fatores de Transcrição/genética , Animais , Anticorpos Antinucleares , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Trióxido de Arsênio , Arsenicais/farmacologia , Autoantígenos , Doenças Autoimunes/tratamento farmacológico , Células CHO , Diferenciação Celular/efeitos dos fármacos , Cricetinae , Células HL-60 , Humanos , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/etiologia , Proteínas de Neoplasias/imunologia , Proteínas de Fusão Oncogênica/imunologia , Óxidos/farmacologia , Proteína da Leucemia Promielocítica , Transfecção , Tretinoína/farmacologia , Proteínas Supressoras de Tumor
19.
Leukemia ; 9(12): 2027-33, 1995 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-8609713

RESUMO

PML has been identified through its fusion to the RAR alpha gene in acute promyelocytic leukemia (APL). The PML protein is specifically associated to nuclear bodies (NBs) whose alterations in APL were proposed to contribute to leukemogenesis. The role of this nuclear domain (which also harbors the Sp100 autoantigen and the NDP52 protein) is unknown. Here, we show that the PML protein, like Sp100 and NDP52, is induced by interferons (IFNs alpha, beta and gamma) in a large variety of human cells. Interestingly, the NBs that contain the three IFN-induced proteins appear to be associated to speckles labelled by the IFN-mediator Mx1. These observations link NBs to IFN response pathways, which may contribute to the elucidation of the biological role of these structures. In APL cells, IFNs induced both PML and PML/RAR alpha expression, resulting in an increased sequestration of PML and RXRs in the microspeckles induced by the fusion protein. As PML has growth suppressing properties, it may mediate some of the antiproliferative effects of IFN. In APL, inactivation of PML may result in disruption of growth control.


Assuntos
Antineoplásicos/farmacologia , Proteínas de Ligação ao GTP , Interferons/farmacologia , Leucemia Promielocítica Aguda/metabolismo , Proteínas de Neoplasias , Proteínas/metabolismo , Fatores de Transcrição/biossíntese , Western Blotting , Humanos , Microscopia Confocal , Proteínas de Resistência a Myxovirus , Proteínas Nucleares/biossíntese , Proteína da Leucemia Promielocítica , Células Tumorais Cultivadas , Proteínas Supressoras de Tumor
20.
Oncogene ; 11(12): 2565-73, 1995 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-8545113

RESUMO

PML is a nuclear matrix protein with growth suppressing properties, whose expression is deregulated during oncogenesis. Moreover, in the t(15;17) translocation of acute promyelocytic leukaemia (APL), PML fusion to the retinoic acid receptor alpha (RAR alpha) is the likely molecular basis of leukaemogenesis. Here we show that interferons (IFNs) alpha, beta, and gamma upregulate PML mRNA expression. Analysis of 5' genomic sequences of the PML gene revealed an IFN-alpha/-beta stimulated response element (ISRE) and an IFN-gamma activation site (GAS) in the untranslated first exon. Binding of IFN signal transducers and activators of transcription (STATs) was demonstrated to be weak for the PML GAS, but strong for the PML ISRE which also seemed to contribute substantially to the IFN-gamma response. Thus, PML is a primary target gene of IFNs and would appear as a suitable candidate for mediating some of their antiproliferative effects. Abnormalities of PML structure, localisation or expression in human malignancy, constitute examples of how an IFN target gene may be altered in oncogenesis.


Assuntos
Interferons/farmacologia , Proteínas de Neoplasias , Proteínas Nucleares , Regiões Promotoras Genéticas , Fatores de Transcrição/genética , Transcrição Gênica/efeitos dos fármacos , Sequência de Aminoácidos , Animais , Sequência de Bases , Células CHO , Cricetinae , Células HeLa , Humanos , Dados de Sequência Molecular , Proteína da Leucemia Promielocítica , Proteínas Supressoras de Tumor
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