Altered expression of the mRNA stability factor HuR promotes cyclooxygenase-2 expression in colon cancer cells.
Cyclooxygenase-2 (COX-2) expression is normally tightly regulated. However, constitutive overexpression plays a key role in colon carcinogenesis. To understand the molecular nature of enhanced COX-2 expression detected in colon cancer, we examined the ability of the AU-rich element-containing (ARE-containing) 3' untranslated region (3'UTR) of COX-2 mRNA to regulate rapid mRNA decay in human colon cancer cells. In tumor cells displaying enhanced growth and tumorigenicity that is correlated with elevated COX-2, vascular endothelial growth factor (VEGF), and IL-8 protein levels, the corresponding mRNAs were transcribed constitutively and turned over slowly. The observed mRNA stabilization is owing to defective recognition of class II-type AREs present within the COX-2, VEGF, and IL-8 3'UTRs; c-myc mRNA, containing a class I ARE decayed rapidly in the same cells. Correlating with cellular defects in mRNA stability, the RNA-binding of trans-acting cellular factors was altered. In particular, we found that the RNA-stability factor HuR binds to the COX-2 ARE, and overexpression of HuR, as detected in tumors, results in elevated expression of COX-2, VEGF, and IL-8. These findings demonstrate the functional significance rapid mRNA decay plays in controlling gene expression and show that dysregulation of these trans-acting factors can lead to overexpression of COX-2 and other angiogenic proteins, as detected in neoplasia.
Dixon
D A
DA
Department of Oncological Sciences, University of Utah, Salt Lake City, Utah, USA. dan.dixon@mcmail.vanderbilt.edu
Tolley
N D
ND
King
P H
PH
Nabors
L B
LB
McIntyre
T M
TM
Zimmerman
G A
GA
Prescott
S M
SM
D020413:3' Untranslated Regions / Q000378:metabolism; D000954:Antigens, Surface; D003110:Colonic Neoplasms / Q000201:enzymology*; D051546:Cyclooxygenase 2; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; D016228:Endothelial Growth Factors / Q000235:genetics; D019073:HT29 Cells; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics; D007527:Isoenzymes / Q000235:genetics*; D008222:Lymphokines / Q000235:genetics; D008565:Membrane Proteins; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D020413:3' Untranslated Regions; D000954:Antigens, Surface; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D016228:Endothelial Growth Factors; D016209:Interleukin-8; D007527:Isoenzymes; D008222:Lymphokines; D008565:Membrane Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D020928:Mitogen-Activated Protein Kinases