AU-rich elements and alternative splicing in the beta-catenin 3'UTR can influence the human beta-catenin mRNA stability.
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.
Thiele
Andrea
A
Hubrecht Laboratory, The Netherlands Institute of Developmental Biology, Uppsalalaan 8, NL-3584 CT Utrecht, The Netherlands. andrea.thiele@han.nl
Nagamine
Yoshikuni
Y
Hauschildt
Sunna
S
Clevers
Hans
H
D020413:3' Untranslated Regions / Q000235:genetics*; D017398:Alternative Splicing / Q000235:genetics*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000737:chemistry; D003593:Cytoplasm / Q000737:chemistry; D004004:Dichlororibofuranosylbenzimidazole / Q000494:pharmacology; D017353:Gene Deletion; D015870:Gene Expression / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D020871:RNA Stability / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D038621:Regulatory Sequences, Ribonucleic Acid / Q000235:genetics*; D051820:TCF Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D051176:beta Catenin / Q000235:genetics*
D020413:3' Untranslated Regions; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D038621:Regulatory Sequences, Ribonucleic Acid; D051820:TCF Transcription Factors; D051176:beta Catenin; D004004:Dichlororibofuranosylbenzimidazole