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Transcriptional and post-transcriptional mechanisms for lysophosphatidic acid-induced cyclooxygenase-2 expression in ovarian cancer cells

Regina A. Oyesanya^*, Zendra P. Lee^*, Jinhua Wu^*, Jing Chen^*, Yuanda Song^*, Abir Mukherjee^*, Paul Dent^*, Tomasz Kordula^*, Huiping Zhou and Xianjun Fang^*,1

^* Department of Biochemistry and Molecular Biology and

Department of Microbiology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA

¹ Correspondence: Virginia Commonwealth University, Department of Biochemistry and Molecular Biology, Box 980614, 1101 East Marshall St., Richmond, VA 23298, USA. E-mail: xfang{at}vcu.edu

Emerging evidence suggests that lysophosphatidic acid (LPA) is a physiological regulator of cyclooxygenase-2 (Cox-2) expression. Herein we used ovarian cancer cells as a model to investigate the molecular mechanisms that link the LPA G protein-coupled receptors (GPCRs) to Cox-2 expression. LPA stimulated Cox-2 expression and release of prostaglandins though the LPA₁, LPA₂, and LPA₅ receptors. The effect of LPA involves both transcriptional activation and post-transcriptional enhancement of Cox-2 mRNA stability. The consensus sites for C/EBP in the Cox-2 promoter were essential for transcriptional activation of Cox-2 by LPA. The NF-B and AP-1 transcription factors commonly involved in inducible Cox-2 expression were dispensable. Dominant-negative C/EPBβ inhibited LPA activation of the Cox-2 promoter and expression. Furthermore, LPA stimulated C/EBPβ phosphorylation and activity through a novel mechanism integrating GPCR signals and a permissive activity from a receptor tyrosine kinase (RTK). This role of RTK was not consistent with LPA activation of C/EBP through transactivation of RTK, as full activation of RTKs with their own agonists only weakly stimulated C/EBP. In addition to the transcriptional activation, the RNA stabilization protein HuR bound to and protected Cox-2 mRNA in LPA-stimulated cells, indicating an active role for HuR in sustaining Cox-2 induction during physiological responses.—Oyesanya, R. A., Lee, Z. P., Wu, J., Chen, J., Song, Y., Mukherjee, A., Dent, P., Kordula, T., Zhou, H., Fang, X. Transcriptional and post-transcriptional mechanisms for lysophosphatidic acid-induced cyclooxygenase-2 expression in ovarian cancer cells.

Key Words: C/EBP • GPCR • HuR • receptor tyrosine kinase