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1.
Mol Endocrinol ; 24(1): 60-75, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19901196

RESUMO

Rhox5, the founding member of the reproductive homeobox on the X chromosome (Rhox) gene cluster, encodes a homeodomain-containing transcription factor that is selectively expressed in Sertoli cells, where it promotes the survival of male germ cells. To identify Rhox5-regulated genes, we generated 15P-1 Sertoli cell clones expressing physiological levels of Rhox5 from a stably transfected expression vector. Microarray analysis identified many genes altered in expression in response to Rhox5, including those encoding proteins controlling cell cycle regulation, apoptosis, metabolism, and cell-cell interactions. Fifteen of these Rhox5-regulated genes were chosen for further analysis. Analysis of Rhox5-null male mice indicated that at least nine of these are Rhox5-regulated in the testes in vivo. Many of them have distinct postnatal expression patterns and are regulated by Rhox5 at different postnatal time points. Most of them are expressed in Sertoli cells, indicating that they are candidates to be directly regulated by Rhox5. Transfection analysis with expression vectors encoding different mouse and human Rhox family members revealed that the regulatory response of a subset of these Rhox5-regulated genes is both conserved and redundant. Given that Rhox5 depends on androgen receptor (AR) for expression in Sertoli cells, we examined whether some Rhox5-regulated genes are also regulated by AR. We provide several lines of evidence that this is the case, leading us to propose that RHOX5 serves as a key intermediate transcription factor that directs some of the actions of AR in the testes.


Assuntos
Androgênios/farmacologia , Regulação da Expressão Gênica , Genes Homeobox , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/fisiologia , Receptores Androgênicos/fisiologia , Células de Sertoli/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/fisiologia , Envelhecimento , Animais , Linhagem Celular , Células Clonais , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas de Homeodomínio/metabolismo , Humanos , Masculino , Camundongos , Camundongos Knockout , Camundongos Mutantes , Análise de Sequência com Séries de Oligonucleotídeos , RNA Mensageiro/metabolismo , Receptores Androgênicos/deficiência , Receptores Androgênicos/genética , Elementos de Resposta/genética , Espermatogênese/genética , Testículo/crescimento & desenvolvimento , Testículo/metabolismo , Fatores de Transcrição/deficiência , Fatores de Transcrição/metabolismo , Transfecção
2.
J Immunol ; 177(7): 4636-43, 2006 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-16982902

RESUMO

Leishmania donovani, a protozoan parasite, inflicts a fatal disease, visceral leishmaniasis. The suppression of antileishmanial T cell responses that characterizes the disease was proposed to be due to deficiency of a T cell growth factor, IL-2. We demonstrate that during the first week after L. donovani infection, IL-2 induces IL-10 that suppresses the host-protective functions of T cells 14 days after infection. The observed suppression is concurrent with increased CD4+ glucocorticoid-induced TNF receptor+ T cells and Foxp3 expression in BALB/c mice, implicating IL-2-dependent regulatory T cell control of antileishmanial immune responses. Indeed, IL-2 and IL-10 neutralization at different time points after the infection demonstrates their distinct roles at the priming and effector phases, respectively, and establishes kinetic modulation of ongoing immune responses as a principle of a rational, phase-specific immunotherapy.


Assuntos
Imunoterapia , Interleucina-10/biossíntese , Interleucina-2/metabolismo , Leishmaniose Visceral/imunologia , Linfócitos T/imunologia , Animais , Antígenos CD4/metabolismo , Relação Dose-Resposta a Droga , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Fatores de Transcrição Forkhead/metabolismo , Interleucina-2/administração & dosagem , Leishmania donovani/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Receptores de Interleucina-2/metabolismo , Receptores do Fator de Necrose Tumoral/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Tempo
4.
Nucleic Acids Res ; 32(4): 1270-8, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-14981150

RESUMO

HIV-1 Tat protein reprograms cellular gene expression of infected as well as uninfected cells apart from its primary function of transactivating HIV-1 long terminal repeat (LTR) promoter by binding to a nascent RNA stem-loop structure known as the transactivator response region (TAR). Tat also induces chromatin remodeling of proviral LTR-mediated gene expression by recruiting histone acetyl transferases to the chromatin, which results in histone acetylation. Furthermore several studies have shown convincing evidence that Tat can transactivate HIV-1 gene expression in the absence of TAR, the molecular mechanism of which remains to be elucidated. Here we show a direct interaction of Tat with nuclear factor kappa B (NFkappaB) enhancer, a global regulatory sequence for many cellular genes both in vitro and in vivo. This interaction not only provides a novel molecular basis to explain TAR-independent transactivation in HIV-1, but also points toward the potential mechanism of Tat- mediated modulation of cellular genes.


Assuntos
Elementos Facilitadores Genéticos , Produtos do Gene tat/metabolismo , HIV-1 , NF-kappa B/metabolismo , Ativação Transcricional , Sequência de Aminoácidos , Sítios de Ligação , Linhagem Celular , Regulação Viral da Expressão Gênica , HIV-1/genética , Humanos , Dados de Sequência Molecular , Alinhamento de Sequência , Sequências Repetidas Terminais , Produtos do Gene tat do Vírus da Imunodeficiência Humana
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