Transcriptional and post-transcriptional mechanisms for lysophosphatidic acid-induced cyclooxygenase-2 expression in ovarian cancer cells.
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.
Oyesanya
Regina A
RA
Virginia Commonwealth University, Department of Biochemistry and Molecular Biology, 1101 East Marshall St., Richmond, VA 23298, USA.
Lee
Zendra P
ZP
Wu
Jinhua
J
Chen
Jing
J
Song
Yuanda
Y
Mukherjee
Abir
A
Dent
Paul
P
Kordula
Tomasz
T
Zhou
Huiping
H
Fang
Xianjun
X
D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism; D016718:Arachidonic Acid / Q000378:metabolism; D001483:Base Sequence; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000235:genetics*; D017931:DNA Primers / Q000235:genetics; D015232:Dinoprostone / Q000096:biosynthesis; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; D005260:Female; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism / Q000494:pharmacology*; D016297:Mutagenesis, Site-Directed; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D012323:RNA Processing, Post-Transcriptional / Q000187:drug effects; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D049368:Receptors, Lysophosphatidic Acid / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects
D000954:Antigens, Surface; D022762:CCAAT-Enhancer-Binding Proteins; D017931:DNA Primers; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D008246:Lysophospholipids; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D049368:Receptors, Lysophosphatidic Acid; D016718:Arachidonic Acid; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D015232:Dinoprostone; C032881:lysophosphatidic acid