期刊
BLOOD
卷 103, 期 6, 页码 2135-2142出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2003-09-3131
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- NHLBI NIH HHS [R01 HL-50675] Funding Source: Medline
- NINDS NIH HHS [P50 NS-23327] Funding Source: Medline
Coactivators p300 and CREB (cyclic adenosine monophosphate [cAMP]-response element binding protein)-binding protein (CBP) serve as an integrator for gene transcription. Their relative involvement in regulating cyclooxygenase-2 (COX-2) promoter activity had not been characterized. Using fibroblast and macrophage COX-2 transcription as a model, we determined p300 and CBP levels in nuclear extracts and their binding to a COX-2 promoter probe. CBP level was barely detectable and there was little CBP binding. In contrast, p300 was detectable in nucleus and its binding to a COX-2 promoter probe was enhanced by phorbol 12-myristate 13-acetate (PMA), Interleukin-1beta (IL-1beta), or lipopolysaccharide (LIPS). Binding of p300/CBP-associated factor (PCAF) was also up-regulated. COX-2 proteins and promoter activities induced by these agonists; were augmented by p300 overexpression. Early region 1A (E1A), but not its deletion mutant, abrogated COX-2 expression induced by inflammatory mediators and with or without p300 overexpression. Molecular analysis of p300 revealed the requirement of multiple domains, including histone acetyltransferase (HAT) for COX-2 transactivation. Furthermore, roscovitine, an Indirect inhibitor of p300 HAT, and histone deacetylase-11 transfection completely abolished COX-2 promoter activity. We conclude that p300 is the predominant coactivator that is essential for COX-2 transcriptional activation by proinflammatory mediators. (C) 2004 by The American Society of Hematology.
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