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1.
Nat Commun ; 3: 633, 2012 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-22252557

RESUMO

Transcription is a multi-stage process that coordinates several steps within the transcription cycle including chromatin reorganization, RNA polymerase II recruitment, initiation, promoter clearance and elongation. Recent advances have identified the super elongation complex, containing the eleven-nineteen lysine-rich leukaemia (ELL) protein, as a key regulator of transcriptional elongation. Here we show that ELL has a diverse and kinetically distinct role before its assembly into the super elongation complex by stabilizing Pol II recruitment/initiation and entry into the pause site. Loss of ELL destabilizes the pre-initiation complexes and results in disruption of early elongation and promoter proximal chromatin structure before recruitment of AFF4 and other super elongation complex components. These changes result in significantly reduced transcriptional activation of rapidly induced genes. Thus, ELL has an early and essential role during rapid high-amplitude gene expression that is required for both Pol II pause site entry and release.


Assuntos
RNA Polimerase II/química , Fatores de Elongação da Transcrição/metabolismo , Sítios de Ligação , Cromatina/química , Imunoprecipitação da Cromatina , Regulação da Expressão Gênica , Células HEK293 , Histonas/química , Humanos , Células Jurkat , Cinética , Modelos Biológicos , Análise de Sequência com Séries de Oligonucleotídeos , Fosforilação , Regiões Promotoras Genéticas , Interferência de RNA , Transcrição Gênica
2.
Cancer Res ; 70(2): 532-42, 2010 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-20068145

RESUMO

The BRCA1 gene product plays numerous roles in regulating genome integrity. Its role in assembling supermolecular complexes in response to DNA damage has been extensively studied; however, much less is understood about its role as a transcriptional coregulator. Loss or mutation is associated with hereditary breast and ovarian cancers, whereas altered expression occurs frequently in sporadic forms of breast cancer, suggesting that the control of BRCA1 transcription might be important to tumorigenesis. Here, we provide evidence of a striking linkage between the roles for BRCA1 as a transcriptional coregulator with control of its expression via an autoregulatory transcriptional loop. BRCA1 assembles with complexes containing E2F-1 and RB to form a repressive multicomponent transcriptional complex that inhibits BRCA1 promoter transcription. This complex is disrupted by genotoxic stress, resulting in the displacement of BRCA1 protein from the BRCA1 promoter and subsequent upregulation of BRCA1 transcription. Cells depleted of BRCA1 respond by upregulating BRCA1 transcripts, whereas cells overexpressing BRCA1 respond by downregulating BRCA1 transcripts. Tandem chromatin immmunoprecipitation studies show that BRCA1 is regulated by a dynamic coregulatory complex containing BRCA1, E2F1, and Rb at the BRCA1 promoter that is disrupted by DNA-damaging agents to increase its transcription. These results define a novel transcriptional mechanism of autoregulated homeostasis of BRCA1 that selectively titrates its levels to maintain genome integrity in response to genotoxic insult.


Assuntos
Proteína BRCA1/biossíntese , Regulação Neoplásica da Expressão Gênica , Genes BRCA1 , Regiões Promotoras Genéticas , Proteína BRCA1/genética , Linhagem Celular Tumoral , Regulação para Baixo , Homeostase , Humanos , Células Jurkat , Masculino , Transcrição Gênica
3.
Proc Natl Acad Sci U S A ; 106(46): 19286-91, 2009 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-19880750

RESUMO

Profiling the dynamic interaction of p300 with proximal promoters of human T cells identified a class of genes that rapidly coassemble p300 and RNA polymerase II (pol II) following mitogen stimulation. Several of these p300 targets are immediate early genes, including FOS, implicating a prominent role for p300 in the control of primary genetic responses. The recruitment of p300 and pol II rapidly transitions to the assembly of several elongation factors, including the positive transcriptional elongation factor (P-TEFb), the bromodomain-containing protein (BRD4), and the elongin-like eleven nineteen lysine-rich leukemia protein (ELL). However, transcription at many of these rapidly induced genes is transient, wherein swift departure of P-TEFb, BRD4, and ELL coincides with termination of transcriptional elongation. Unexpectedly, both p300 and pol II remain accumulated or "bookmarked" at the proximal promoter long after transcription has terminated, demarking a clear mechanistic separation between the recruitment and elongation phases of transcription in vivo. The bookmarked pol II is depleted of both serine-2 and serine-5 phosphorylation of its C-terminal domain and remains proximally positioned at the promoter for hours. Surprisingly, these p300/pol II bookmarked genes can be readily reactivated, and elongation factors can be reassembled by subsequent addition of nonmitogenic agents that, alone, have minimal effects on transcription in the absence of prior preconditioning by mitogen stimulation. These findings suggest that p300 is likely to play an important role in biological processes in which transcriptional bookmarking or preconditioning influences cellular growth and development through the dynamic priming of genes for response to rechallenge by secondary stimuli.


Assuntos
Proteína p300 Associada a E1A/metabolismo , Regulação da Expressão Gênica , RNA Polimerase II/metabolismo , Subpopulações de Linfócitos T/metabolismo , Linhagem Celular , Estudo de Associação Genômica Ampla , Humanos , Memória Imunológica/genética , Mitógenos/farmacologia , Regiões Promotoras Genéticas , Subpopulações de Linfócitos T/efeitos dos fármacos , Transcrição Gênica , Fatores de Elongação da Transcrição/metabolismo
4.
Mol Pharmacol ; 74(3): 872-83, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18556456

RESUMO

2-(2,4-Difluoro-phenyl)-4,5,6,7-tetrafluoro-1H-isoindole-1,3(2H)-dione (CPS49) is a member of a recently identified class of redox-reactive thalidomide analogs that show selective killing of leukemic cells by increasing intracellular reactive oxygen species (ROS) and targeting multiple transcriptional pathways. Flavopiridol is a semisynthetic flavonoid that inhibits cyclin-dependent kinases and also shows selective lethality against leukemic cells. The purpose of this study is to explore the efficacy and mechanism of action of the combinatorial use of the redox-reactive thalidomide CPS49 and the cyclin-dependent kinase inhibitor flavopiridol as a selective antileukemic therapeutic strategy. In combination, CPS49 and flavopiridol were found to induce selective cytotoxicity associated with mitochondrial dysfunction and elevations of ROS in leukemic cells ranging from additive to synergistic activity at low micromolar concentrations. Highest synergy was observed at the level of ROS generation with a strong correlation between cell-specific cytotoxicity and reciprocal coupling of drug-induced ROS elevation with glutathione depletion. Examination of the transcriptional targeting of CPS49 and flavopiridol combinations reveals that the drugs act in concert to initiate a cell specific transcriptional program that manipulates nuclear factor-kappaB (NF-kappaB), E2F-1, and p73 activity to promote enhanced mitochondrial instability by simultaneously elevating the expression of the proapoptotic factors BAX, BAD, p73, and PUMA while depressing expression of the antiapoptotic genes MCL1, XIAP, BCL-xL, SURVIVIN, and MDM2. The coadministration of CPS49 and flavopiridol acts through coordinate targeting of transcriptional pathways that enforce selective mitochondrial dysfunction and ROS elevation and is therefore a promising new therapeutic combination that warrants further preclinical exploration.


Assuntos
Antineoplásicos/farmacologia , Flavonoides/farmacologia , Homeostase/efeitos dos fármacos , Leucemia/patologia , Mitocôndrias/efeitos dos fármacos , Piperidinas/farmacologia , Talidomida/análogos & derivados , Proteínas Reguladoras de Apoptose/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Sequestradores de Radicais Livres/farmacologia , Glutationa/metabolismo , Humanos , Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , NF-kappa B/metabolismo , Proteínas Nucleares/metabolismo , Especificidade de Órgãos/efeitos dos fármacos , Oxirredução/efeitos dos fármacos , Proteínas Proto-Oncogênicas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Talidomida/farmacologia , Transcrição Gênica/efeitos dos fármacos , Proteínas Supressoras de Tumor/metabolismo
5.
Am J Pathol ; 172(2): 495-509, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18187569

RESUMO

Global genomic approaches in cancer research have provided new and innovative strategies for the identification of signatures that differentiate various types of human cancers. Computational analysis of the promoter composition of the genes within these signatures may provide a powerful method for deducing the regulatory transcriptional networks that mediate their collective function. In this study we have systematically analyzed the promoter composition of gene classes derived from previously established genetic signatures that recently have been shown to reliably and reproducibly distinguish five molecular subtypes of breast cancer associated with distinct clinical outcomes. Inferences made from the trends of transcription factor binding site enrichment in the promoters of these gene groups led to the identification of regulatory pathways that implicate discrete transcriptional networks associated with specific molecular subtypes of breast cancer. One of these inferred pathways predicted a role for nuclear factor-kappaB in a novel feed-forward, self-amplifying, autoregulatory module regulated by the ERBB family of growth factor receptors. The existence of this pathway was verified in vivo by chromatin immunoprecipitation and shown to be deregulated in breast cancer cells overexpressing ERBB2. This analysis indicates that approaches of this type can provide unique insights into the differential regulatory molecular programs associated with breast cancer and will aid in identifying specific transcriptional networks and pathways as potential targets for tumor subtype-specific therapeutic intervention.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Redes Reguladoras de Genes/genética , Regiões Promotoras Genéticas/genética , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina , Análise por Conglomerados , Progressão da Doença , Feminino , Genes Neoplásicos , Humanos , Análise de Componente Principal
6.
Hum Mutat ; 28(8): 824-9, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17431880

RESUMO

Multiple variants of the vascular adhesion molecule-1 (VCAM1) promoter show increased nucleotide heterozygosity in the African American population. Using a novel transfection-based transcriptional pathway profiling method, we show that select uncommon variants are functionally hyperactive. Eight candidate VCAM1 promoter haplotypes comprising 13 previously identified SNPs were assessed for response to known mitogens. Activity was correlated with bioinformatic analysis of hyper- and hyporesponsive variants to identify the gain or loss of haplotype-specific transcription factor binding site (TFBS). Using this approach, a low frequency regulatory allele (c.-540A>G; dbSNP rs3783605:A>G), found in a hyperactive VCAM1 promoter haplotype, was shown to create a candidate binding site for ETS2 that was confirmed in vivo by chromatin immunoprecipitation. This report provides the first functional evaluation of VCAM1 promoter polymorphisms and establishes a hypothetical foundation for investigation of their role in the pathogenesis of VCAM1-associated diseases that disproportionately afflict African Americans, including thromboembolic diseases, asthma, and multiple myeloma.


Assuntos
Negro ou Afro-Americano/genética , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas/genética , Molécula 1 de Adesão de Célula Vascular/genética , Sequência de Bases , Haplótipos , Humanos , Células Jurkat , Mitógenos/farmacologia , Dados de Sequência Molecular , Transcrição Gênica/efeitos dos fármacos
7.
Blood ; 108(13): 4126-35, 2006 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-16940421

RESUMO

Using a novel cell-based assay to profile transcriptional pathway targeting, we have identified a new functional class of thalidomide analogs with distinct and selective antileukemic activity. These agents activate nuclear factor of activated T cells (NFAT) transcriptional pathways while simultaneously repressing nuclear factor-kappaB (NF-kappaB) via a rapid intracellular amplification of reactive oxygen species (ROS). The elevated ROS is associated with increased intracellular free calcium, rapid dissipation of the mitochondrial membrane potential, disrupted mitochondrial structure, and caspase-independent cell death. This cytotoxicity is highly selective for transformed lymphoid cells, is reversed by free radical scavengers, synergizes with the antileukemic activity of other redox-directed compounds, and preferentially targets cells in the S phase of the cell cycle. Live-cell imaging reveals a rapid drug-induced burst of ROS originating in the endoplasmic reticulum and associated mitochondria just prior to spreading throughout the cell. As members of a novel functional class of "redoxreactive" thalidomides, these compounds provide a new tool through which selective cellular properties of redox status and intracellular bioactivation can be leveraged by rational combinatorial therapeutic strategies and appropriate drug design to exploit cell-specific vulnerabilities for maximum drug efficacy.


Assuntos
Sinalização do Cálcio/efeitos dos fármacos , Imunossupressores/farmacologia , Leucemia/imunologia , Talidomida/farmacologia , Sinalização do Cálcio/imunologia , Morte Celular/efeitos dos fármacos , Morte Celular/imunologia , Linhagem Celular Transformada , Avaliação Pré-Clínica de Medicamentos/métodos , Retículo Endoplasmático/imunologia , Humanos , Imunidade Celular/efeitos dos fármacos , Imunidade Celular/imunologia , Imunossupressores/uso terapêutico , Leucemia/tratamento farmacológico , Mitocôndrias/imunologia , NF-kappa B/imunologia , Fatores de Transcrição NFATC/imunologia , Oxirredução/efeitos dos fármacos , Espécies Reativas de Oxigênio/imunologia , Talidomida/análogos & derivados , Talidomida/uso terapêutico
8.
BMC Bioinformatics ; 6: 259, 2005 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-16232321

RESUMO

BACKGROUND: The purpose of this study is to determine whether or not there exists nonrandom grouping of cis-regulatory elements within gene promoters that can be perceived independent of gene expression data and whether or not there is any correlation between this grouping and the biological function of the gene. RESULTS: Using ProSpector, a web-based promoter search and annotation tool, we have applied an unbiased approach to analyze the transcription factor binding site frequencies of 1400 base pair genomic segments positioned at 1200 base pairs upstream and 200 base pairs downstream of the transcriptional start site of 7298 commonly studied human genes. Partitional clustering of the transcription factor binding site composition within these promoter segments reveals a small number of gene groups that are selectively enriched for gene ontology terms consistent with distinct aspects of cellular function. Significance ranking of the class-determining transcription factor binding sites within these clusters show substantial overlap between the gene ontology terms of the transcriptions factors associated with the binding sites and the gene ontology terms of the regulated genes within each group. CONCLUSION: Thus, gene sorting by promoter composition alone produces partitions in which the "regulated" and the "regulators" cosegregate into similar functional classes. These findings demonstrate that the transcription factor binding site composition is non-randomly distributed between gene promoters in a manner that reflects and partially defines general gene class function.


Assuntos
Expressão Gênica/fisiologia , Regiões Promotoras Genéticas/genética , Fatores de Transcrição/metabolismo , Sítios de Ligação , Fenômenos Fisiológicos Celulares , Humanos , Terminologia como Assunto
9.
Biochem Biophys Res Commun ; 323(1): 355-60, 2004 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-15351744

RESUMO

High throughput technologies are standard methods for analysis of the proteome. Multi-layer multi-well plate dot-blotting system (MLDot) technology is a high-throughput dot blotting system that provides a simple, cost-effective approach for protein expression profiling in multiple samples. In contrast to traditional dot blot, MLDot uses a layered stack of thin, sieve-like membranes in place of a single nitrocellulose membrane. Therefore, up to 10 membranes can be prepared from the samples arrayed in a single 96-well plate. We describe the ability of MLDot to detect the predicted changes in protein expression following multiple mitogen treatment of T-cells. We compare the levels of the phopshorylated forms of CREB, Jun, and Akt in Jurkat T-cells as detected by MLDot to those measured by a gel-based assay. We also describe the ability of MLDot to detect differences in the levels of phosphorylated Akt in Jurkat cells as compared to primary lymphocytes.


Assuntos
Análise Serial de Proteínas/métodos , Biotinilação , Western Blotting , Membrana Celular/metabolismo , Desenho de Fármacos , Humanos , Células Jurkat , Linfócitos/metabolismo , Mitógenos , Fosforilação , Mapeamento de Interação de Proteínas , Proteoma , Transdução de Sinais , Espectrometria de Fluorescência , Linfócitos T/metabolismo
10.
Proc Natl Acad Sci U S A ; 101(32): 11554-9, 2004 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-15286281

RESUMO

Understanding the language encrypted in the gene regulatory regions of the human genome is a challenging goal for the genomic era. Although customary extrapolations from steady-state mRNA levels have been effective, deciphering these regulatory codes will require additional empirical data sets that more closely reflect the dynamic progression of molecular events responsible for inducible transcription. We describe an approach using chromatin immunoprecipitation to profile the kinetic occupancy of the transcriptional coactivator and histone acetyltransferase p300 at numerous mitogen-induced genes in activated T cells. Comparison of these profiles reveals a class of promoters that share common patterns of inducible expression, p300 recruitment, dependence on selective p300 domains, and sensitivity to histone deacetylase inhibitors. Remarkably, this class also shares an evolutionarily conserved promoter composition and structure that accurately predicts additional human genes with similar functional attributes. This "reverse genomic" approach will have broad application for the genome-wide classification of promoter structure and function.


Assuntos
Acetiltransferases/metabolismo , Proteínas de Ciclo Celular/metabolismo , Biologia Computacional/métodos , Regiões Promotoras Genéticas/genética , Sequência Conservada , Regulação da Expressão Gênica/efeitos dos fármacos , Histona Acetiltransferases , Humanos , Células Jurkat , Cinética , Ativação Linfocitária , Mitógenos/farmacologia , Regiões Promotoras Genéticas/fisiologia , Ligação Proteica/efeitos dos fármacos , Transporte Proteico , Sequências Reguladoras de Ácido Nucleico , Linfócitos T/metabolismo , Fatores de Transcrição , Fatores de Transcrição de p300-CBP
11.
Biotechniques ; 36(6): 1046-51, 2004 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15211757

RESUMO

The molecular profiles of protein expression from hundreds of cell lysates can be determined in a high-throughput manner by using fluorescent bead technologies, enzyme-linked immunosorbent assays (ELISAs), and protein microarrays. Although powerful, these tools are costly and technically challenging and thus have limited accessibility for many research groups. We propose a modification of traditional dot blotting that increases throughput of this approach and provides a simple and cost-effective technique for profiling multiple samples. In contrast to traditional blotting that uses a single membrane, we introduce blotting onto a stack of novel, thin, sieve-like membranes. These membranes have a high affinity for binding proteins, but have a lower capacity of protein binding compared to traditional (nitrocellulose) membranes. We compare the linear binding capacity and variability of these novel membranes with nitrocellulose membranes. Also, we describe the use of these membranes in a multilayer dot blot format for profiling mitogen-mediated signal transduction pathways in T cells.


Assuntos
Immunoblotting/métodos , Mapeamento de Interação de Proteínas/métodos , Proteoma/análise , Proteoma/metabolismo , Proteômica/métodos , Proteínas Sanguíneas/análise , Proteínas Sanguíneas/metabolismo , Humanos , Linfócitos/metabolismo , Membranas Artificiais
12.
J Biol Chem ; 278(42): 41034-46, 2003 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-12896977

RESUMO

The proximal promoter sequence of the interleukin-2 (IL-2) gene contains a series of composite sites or modules that controls much of its responsiveness to environmental stimuli. The integrated targeting of these modules is therefore a major mode of regulation. This report describes how multiple functional hierarchies, required for the recruitment of the p300 co-activator to the CD28RE/AP1 (TRE) module of the IL-2 promoter, are selectively disrupted in human T-cells by the immunosuppressive and anti-inflammatory actions of the p38 mitogen-activated protein kinase inhibitor (MAPK), SB203580. The molecular hierarchies targeted by SB203580 include the combinatorial interaction of NF-kappaB and CREB at the CD28RE/AP1 element coupled with the subsequent dynamic co-assembly and activation of p300. Several aspects of this targeting are linked to the ability of SB203580 to inhibit p38 MAPK-controlled pathways. Together, these results provide the molecular basis through which the combinatorial structure and context of the composite elements of the IL-2 promoter dictates mitogen responsiveness and drug susceptibility that are quantitatively and qualitatively distinct from the isolated action of single consensus sequences and/or transcriptional motifs.


Assuntos
Transcrição Gênica , Motivos de Aminoácidos , Sequência de Bases , Linhagem Celular , Núcleo Celular/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Humanos , Imidazóis/farmacologia , Interleucina-2/metabolismo , Células Jurkat , Sistema de Sinalização das MAP Quinases , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Modelos Estatísticos , Dados de Sequência Molecular , Fosforilação , Plasmídeos/metabolismo , Testes de Precipitina , Regiões Promotoras Genéticas , Piridinas/farmacologia , Transdução de Sinais , Linfócitos T/metabolismo , Fatores de Tempo , Ativação Transcricional , Transfecção , Proteínas Quinases p38 Ativadas por Mitógeno
13.
J Biol Chem ; 278(4): 2249-55, 2003 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-12427762

RESUMO

Although extensive homology exists between related genes p53 and p73, recent data suggest that the family members have divergent roles. We demonstrate that the differential regulatory roles of p53 family member p73 are highly cell-context and promoter-specific. Full-length p73 expressed in the transformed leukemia cell line Jurkat behaves as a specific dominant negative transcriptional repressor of the cell cycle inhibitor gene p21 and blocks p53-mediated apoptosis. These findings provide evidence for a new mechanism in oncogenesis through which the functional properties of p73 can be altered in an inheritable and cell-specific fashion independent of transcriptional coding.


Assuntos
Apoptose , Proteínas de Ligação a DNA/fisiologia , Genes Dominantes , Leucemia/metabolismo , Proteínas Nucleares/fisiologia , Caspase 3 , Caspases/metabolismo , Linhagem Celular , Linhagem Celular Transformada , Núcleo Celular/metabolismo , DNA/metabolismo , Proteínas de Ligação a DNA/metabolismo , Ativação Enzimática , Genes Supressores de Tumor , Humanos , Marcação In Situ das Extremidades Cortadas , Células Jurkat , Luciferases/metabolismo , Microscopia de Fluorescência , Proteínas Nucleares/metabolismo , Plasmídeos/metabolismo , Regiões Promotoras Genéticas , Ligação Proteica , Transcrição Gênica , Ativação Transcricional , Transfecção , Proteína Tumoral p73 , Proteína Supressora de Tumor p53/metabolismo , Proteínas Supressoras de Tumor
14.
J Immunol ; 169(12): 6767-78, 2002 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-12471108

RESUMO

In this study, we demonstrate that p53 directly inhibits expression of the T cell growth factor (IL-2) in activated T cells. This repression is independent of the intrinsic transcriptional activity of p53 and is mediated by the Tax-responsive CD28RE-3'-12-O-tetradecanoylphorbol-13-acetate response element (AP1) element of the IL-2 promoter. Coexpression of the Tax oncogene causes full reversal of this repression through coordinate targeting of p300, CREB, and the NF-kappaB pathways. Paradoxically, IL-2 repression by p53 is not reversed by mdm2. Instead, mdm2 represses the IL-2 promoter by a mechanism that is synergistic with p53 and resistant to Tax reversal. The p300 structure-function studies show that these effects are linked to competitive associations among p53, Tax, and mdm2 with multiple domains of p300. The functional outcome of these antagonistic associations is revealed further by the observation that Tax and p53 induce apoptosis in activated T cells through separate and mutually exclusive pathways. Interestingly, both pathways are abrogated by mdm2. These results provide evidence that a dynamic interplay, between Tax and specific elements of the p53 network, mediates growth factor expression and programmed cell death in activated T cells.


Assuntos
Regulação da Expressão Gênica/imunologia , Genes pX/fisiologia , Interleucina-2/biossíntese , Proteína Supressora de Tumor p53/fisiologia , Apoptose/genética , Apoptose/imunologia , Antígenos CD28/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Relação Dose-Resposta Imunológica , Sinergismo Farmacológico , Humanos , Interleucina-2/antagonistas & inibidores , Interleucina-2/genética , Interleucina-2/fisiologia , Células Jurkat , Ativação Linfocitária/genética , NF-kappa B/genética , NF-kappa B/metabolismo , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/fisiologia , Regiões Promotoras Genéticas/imunologia , Processamento de Proteína Pós-Traducional/imunologia , Proteínas Proto-Oncogênicas/fisiologia , Proteínas Proto-Oncogênicas c-mdm2 , Elementos de Resposta/efeitos dos fármacos , Elementos de Resposta/imunologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Acetato de Tetradecanoilforbol/metabolismo , Transativadores/antagonistas & inibidores , Transativadores/fisiologia , Fator de Transcrição AP-1/fisiologia , Transcrição Gênica/imunologia , Proteína Supressora de Tumor p53/antagonistas & inibidores
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