AU-rich elements and alternative splicing in the beta-catenin 3'UTR can influence the human beta-catenin mRNA stability

Exp Cell Res. 2006 Jul 15;312(12):2367-78. doi: 10.1016/j.yexcr.2006.03.029. Epub 2006 Apr 15.

Abstract

Beta-catenin, the central player of the Wnt signaling cascade, is a well-known oncogene. The regulation of beta-catenin protein stability has been studied extensively while other mechanisms that control cellular levels of beta-catenin have hardly been addressed. In this study, we show that there are three beta-catenin mRNA splice variants that differ solely in their 3'-untranslated region (3'UTR) due to alternative splicing or retaining of an intron. The three isoforms were found to be ubiquitously expressed though in different quantities. Upon induction of the beta-catenin protein in peripheral blood mononuclear leukocytes (PBMC), the beta-catenin mRNA is induced in an isoform-specific manner. All three variants occur in the cytoplasm and contribute to the synthesis of beta-catenin acting as a transcriptional coactivator but have different cytoplasmic stabilities in Hela cells. AU-rich elements (AREs), sequence elements implicated in the regulation of mRNA stability, are found in each of the three transcripts. Surprisingly, the AREs contribute to stabilization of the beta-catenin mRNA transcripts in a splicing-dependent manner. The isoform most affected is the one found to be most induced when beta-catenin protein accumulates. These results suggest that alternative splicing and AREs can act together in regulating beta-catenin mRNA stability and thereby provide a step of controlling the cellular beta-catenin concentration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / genetics*
  • Alternative Splicing / genetics*
  • Cell Line, Tumor
  • Cell Nucleus / chemistry
  • Cytoplasm / chemistry
  • Dichlororibofuranosylbenzimidazole / pharmacology
  • Gene Deletion
  • Gene Expression / genetics
  • HeLa Cells
  • Humans
  • Leukocytes, Mononuclear / metabolism
  • RNA Stability / genetics*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / genetics
  • Regulatory Sequences, Ribonucleic Acid / genetics*
  • TCF Transcription Factors / genetics
  • TCF Transcription Factors / metabolism
  • Transcription, Genetic / drug effects
  • Transfection
  • beta Catenin / genetics*

Substances

  • 3' Untranslated Regions
  • RNA, Messenger
  • RNA, Small Interfering
  • Regulatory Sequences, Ribonucleic Acid
  • TCF Transcription Factors
  • beta Catenin
  • Dichlororibofuranosylbenzimidazole