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1.
EMBO J ; 24(1): 85-96, 2005 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-15616592

RESUMO

Nuclear factor kappaB (NF-kappaB) plays an important role in the transcriptional regulation of genes involved in inflammation and cell survival. Here, we show that coactivator-associated arginine methyltransferase CARM1/PRMT4 is a novel transcriptional coactivator of NF-kappaB and functions as a promoter-specific regulator of NF-kappaB recruitment to chromatin. Carm1 knockout cells showed impaired expression of a subset of NF-kappaB-dependent genes upon TNFalpha or LPS stimulation. CARM1 forms a complex with p300 and NF-kappaB in vivo and interacts directly with the NF-kappaB subunit p65 in vitro. CARM1 seems to act in a gene-specific manner mainly by enhancing NF-kappaB recruitment to cognate sites. Moreover, CARM1 synergistically coactivates NF-kappaB-mediated transactivation, in concert with the transcriptional coactivators p300/CREB-binding protein and the p160 family of steroid receptor coactivators. For at least a subset of CARM1-dependent NF-kappaB target genes, the enzymatic activities of both CARM1 and p300 are necessary for the observed synergy between CARM1 and p300. Our results suggest that the cooperative action between protein arginine methyltransferases and protein lysine acetyltransferases regulates NF-kappaB-dependent gene activation in vivo.


Assuntos
Regulação da Expressão Gênica , NF-kappa B/metabolismo , Regiões Promotoras Genéticas , Proteína-Arginina N-Metiltransferases/metabolismo , Animais , Linhagem Celular , Quimiocina CXCL10 , Quimiocina CXCL2 , Quimiocinas/genética , Quimiocinas/metabolismo , Quimiocinas CXC/genética , Quimiocinas CXC/metabolismo , Proteína p300 Associada a E1A , Histonas/metabolismo , Humanos , Lipopolissacarídeos/metabolismo , Substâncias Macromoleculares , Camundongos , Camundongos Knockout , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Coativador 2 de Receptor Nuclear , Proteína-Arginina N-Metiltransferases/genética , Transdução de Sinais/fisiologia , Transativadores/genética , Transativadores/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Ativação Transcricional , Fator de Necrose Tumoral alfa/metabolismo
2.
J Biol Chem ; 278(46): 45145-53, 2003 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-12960163

RESUMO

Nuclear factor kappaB (NF-kappaB) plays an important role in the transcriptional regulation of genes involved in inflammation and cell survival. In this study, we demonstrated that NF-kappaB-dependent gene expression was inhibited by E1A in poly(ADP)-ribose polymerase-1 knock out (PARP-1 (-/-)) cells complemented with wild type PARP-1 after tumor necrosis factor alpha (TNFalpha) or lipopolysaccharide (LPS) treatment. PARP-1 and p300 synergistically coactivated NF-kappaB-dependent gene expression in response to TNFalpha and LPS. Furthermore, PARP-1 interacted directly with p300 and enhanced the interaction of NF-kappaB1/p50 to p300. The C terminus, harboring the catalytic domain of PARP-1 but not its enzymatic activity, was required for complete transcriptional coactivation of NF-kappaB by p300 in response to TNFalpha and LPS. Together, these results indicate that PARP-1 acts synergistically with p300 and plays an essential regulatory role in NF-kappaB-dependent gene expression.


Assuntos
Regulação Enzimológica da Expressão Gênica , NF-kappa B/metabolismo , Proteínas Nucleares/metabolismo , Poli(ADP-Ribose) Polimerases/metabolismo , Transativadores/metabolismo , Ativação Transcricional , Animais , Linhagem Celular , Núcleo Celular/metabolismo , Sobrevivência Celular , Células Cultivadas , Proteína p300 Associada a E1A , Fibroblastos/metabolismo , Glutationa Transferase/metabolismo , Células HeLa , Humanos , Immunoblotting , Lipopolissacarídeos/metabolismo , Camundongos , Camundongos Knockout , Mutação , Plasmídeos/metabolismo , Testes de Precipitina , Ligação Proteica , Estrutura Terciária de Proteína , Transfecção
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