Lysophosphatidylcholine phosphorylates CREB and activates the jun2TRE site of c-jun promoter in vascular endothelial cells.
FEBS Lett
; 457(2): 241-5, 1999 Aug 27.
Article
em En
| MEDLINE
| ID: mdl-10471787
ABSTRACT
Lysophosphatidylcholine (lyso-PC), a polar phospholipid increased in atherogenic lipoproteins and atherosclerotic lesions, has been shown to induce transcription of a variety of endothelial genes relevant to atherogenesis. Lyso-PC has been shown to activate c-jun N-terminal kinase (JNK) and activator protein 1 (AP-1) and thereby stimulate transcription of the c-jun gene. Here we provide evidence that lyso-PC can phosphorylate cyclic AMP responsive element binding protein (CREB) and thereby activate the jun2 12-O-tetradecanoylphorbol 13-acetate response element (jun2TRE) site of the c-jun promoter, which appears to be the major molecular mechanism involved in lyso-PC-induced c-jun gene expression in cultured bovine aortic endothelial cells (BAEC). Transient transfection of BAEC with a 1.6-kbp c-jun promoter and luciferase reporter fusion gene resulted in a 12.9-fold increase in luciferase activity by lyso-PC treatment. Serial deletion mutation in c-jun promoter and luciferase reporter gene assay revealed that the 5' promoter region between nucleotide numbers -268 and -127, which contains a jun2TRE binding sequence, was most crucial for lyso-PC-induced transcription. The 5' promoter region between -76 and -27, which contains an AP-1 site, also affected lyso-PC-induced transcription of the c-jun gene. Point mutation in the jun2TRE site reduced lyso-PC-induced transcription of the c-jun promoter-luciferase fusion gene by a 70.3% decrease in c-jun promoter activity. Electrophoretic mobility shift assays showed increased binding of (32)P-labeled oligonucleotides with jun2TRE in nuclear extracts isolated from lyso-PC-treated BAEC, which was abolished or supershifted by anti-CREB antibody. Immunoblotting with anti-phosphorylated CREB antibody showed rapid phosphorylation of this protein after lyso-PC treatment. These results indicate that lyso-PC phosphorylates CREB, which was then bound to the jun2TRE site of the c-jun promoter and activated transcription. Activation of jun2TRE may play a key role in the transcriptional activation of c-jun as well as other endothelial genes depending upon these transcription factors.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Endotélio Vascular
/
Lisofosfatidilcolinas
/
Regulação da Expressão Gênica
/
Regiões Promotoras Genéticas
/
Genes jun
/
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico
Limite:
Animals
Idioma:
En
Revista:
FEBS Lett
Ano de publicação:
1999
Tipo de documento:
Article
País de afiliação:
Japão