Abstract
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-kappaB and AP-1 transcription factors commonly involved in inducible Cox-2 expression were dispensable. Dominant-negative C/EPBbeta inhibited LPA activation of the Cox-2 promoter and expression. Furthermore, LPA stimulated C/EBPbeta 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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Antigens, Surface / genetics
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Antigens, Surface / metabolism
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Arachidonic Acid / metabolism
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Base Sequence
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CCAAT-Enhancer-Binding Proteins / metabolism
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Cell Line, Tumor
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Cyclooxygenase 2 / genetics*
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DNA Primers / genetics
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Dinoprostone / biosynthesis
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ELAV Proteins
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ELAV-Like Protein 1
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Female
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Humans
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Lysophospholipids / metabolism
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Lysophospholipids / pharmacology*
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Mutagenesis, Site-Directed
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Ovarian Neoplasms / genetics*
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Ovarian Neoplasms / metabolism*
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Phosphorylation / drug effects
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RNA Processing, Post-Transcriptional / drug effects
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RNA Stability / drug effects
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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RNA, Neoplasm / genetics
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RNA, Neoplasm / metabolism
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RNA, Small Interfering / genetics
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RNA-Binding Proteins / antagonists & inhibitors
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RNA-Binding Proteins / genetics
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RNA-Binding Proteins / metabolism
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Receptor Protein-Tyrosine Kinases / metabolism
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Receptors, Lysophosphatidic Acid / antagonists & inhibitors
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Receptors, Lysophosphatidic Acid / genetics
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Receptors, Lysophosphatidic Acid / metabolism
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Sequence Deletion
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Signal Transduction / drug effects
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Transcriptional Activation / drug effects
Substances
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Antigens, Surface
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CCAAT-Enhancer-Binding Proteins
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DNA Primers
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ELAV Proteins
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ELAV-Like Protein 1
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ELAVL1 protein, human
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Lysophospholipids
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RNA, Messenger
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RNA, Neoplasm
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RNA, Small Interfering
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RNA-Binding Proteins
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Receptors, Lysophosphatidic Acid
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Arachidonic Acid
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Cyclooxygenase 2
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PTGS2 protein, human
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Receptor Protein-Tyrosine Kinases
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Dinoprostone
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lysophosphatidic acid