Dynamic regulation of cyclooxygenase-2 promoter activity by isoforms of CCAAT/enhancer-binding proteins

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Abstract

To elucidate the mechanism by which isoforms of CCAAT/enhancer-binding proteins regulate cyclooxygenase-2 expression, we determined by a novel technique binding of six isoforms of this transactivator to two sequence-specific CCAAT/enhancer-binding protein (-132/-125) and cyclic AMP (-59/-53) regulatory elements in human foreskin fibroblasts treated with phorbol 12-myristate 13-acetate for 4 h. The δ isoform bound to these two elements at basal state, which was displaced by full-length as well as two truncated β isoforms, a 41-kDa liver-enriched activating protein and a 16-kDa liver-enriched inhibitory protein, after phorbol ester stimulation. Kinetic analysis shows time-dependent changes in β and δ binding that were concordant with time-dependent increase in cyclooxygenase-2 induction. Overexpression of the 16-kDa β isoform blocked the promoter activity and protein level induced by phorbol ester. Paradoxically, it increased binding of β isoforms to the sequence-specific promoter DNA but suppressed cyclooxygenase-2 promoter activation by p300 cotransfection. These findings provide new insight into the regulation of cyclooxygenase-2 promoter by an interplay between two opposite β isoforms and p300 co-activator.

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Zhu, Y., Saunders, M. A., Yeh, H., Deng, W. G., & Wu, K. K. (2002). Dynamic regulation of cyclooxygenase-2 promoter activity by isoforms of CCAAT/enhancer-binding proteins. Journal of Biological Chemistry, 277(9), 6923–6928. https://doi.org/10.1074/jbc.M108075200

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