Premium
Transcriptional and post‐transcriptional mechanisms for lysophosphatidic acid‐induced cyclooxygenase‐2 expression in ovarian cancer cells
Author(s) -
Oyesanya Regina A.,
Lee Zendra P.,
Wu Jinhua,
Chen Jing,
Song Yuanda,
Mukherjee Abir,
Dent Paul,
Kordula Tomasz,
Zhou Huiping,
Fang Xianjun
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.07-101428
Subject(s) - lysophosphatidic acid , transactivation , microbiology and biotechnology , receptor tyrosine kinase , receptor , g protein coupled receptor , phosphorylation , signal transduction , biology , chemistry , cancer research , transcription factor , biochemistry , gene
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 LPA 1 , LPA 2 , and LPA 5 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‐ΚB 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. FASEB J. 22, 2639–2651 (2008)