Altered expression of the mRNA stability factor HuR promotes cyclooxygenase-2 expression in colon cancer cells.

Academic Article

Abstract

  • 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.
  • Published In

    Keywords

  • 3' Untranslated Regions, Antigens, Surface, Colonic Neoplasms, Cyclooxygenase 2, ELAV Proteins, ELAV-Like Protein 1, Endothelial Growth Factors, HT29 Cells, Humans, Interleukin-8, Isoenzymes, Lymphokines, Membrane Proteins, Mitogen-Activated Protein Kinases, Phosphorylation, Prostaglandin-Endoperoxide Synthases, RNA, Messenger, RNA-Binding Proteins, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factors
  • Digital Object Identifier (doi)

    Author List

  • Dixon DA; Tolley ND; King PH; Nabors LB; McIntyre TM; Zimmerman GA; Prescott SM
  • Start Page

  • 1657
  • End Page

  • 1665
  • Volume

  • 108
  • Issue

  • 11