The Wnt/beta-catenin-->Pitx2 pathway controls the turnover of Pitx2 and other unstable mRNAs.
The Wnt/beta-catenin pathway rapidly induces the transcription of the cell-type-restricted transcription factor Pitx2 that is required for effective cell-specific proliferation activating growth-regulating genes. Here we report that Pitx2 mRNA displays a rapid turnover rate and that activation of the Wnt/beta-catenin pathway stabilizes Pitx2 mRNA as well as other unstable mRNAs, including c-Jun, Cyclin D1, and Cyclin D2, encoded by critical transcriptional target genes of the same pathway. Our data indicate that Pitx2 mRNA stabilization is due to a reduced interaction of Pitx2 3'UTR with the destabilizing AU-rich element (ARE) binding proteins (BPs) KSRP and TTP as well as to an increased interaction with a stabilizing ARE-BP, HuR. Pitx2 itself is a mediator of Wnt/beta-catenin-induced mRNA stabilization. Our previous and present data support the hypothesis that a single pathway can coordinately regulate sequential transcriptional and posttranscriptional events leading to an integrated functional gene regulatory network.
Briata
Paola
P
Istituto Nazionale per la Ricerca sul Cancro (IST), 16132 Genova, Italy.
Ilengo
Cristina
C
Corte
Giorgio
G
Moroni
Christoph
C
Rosenfeld
Michael G
MG
Chen
Ching-Yi
CY
Gherzi
Roberto
R
D020413:3' Untranslated Regions; D000818:Animals; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009687:Nuclear Proteins; D016366:Open Reading Frames; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; D000097577:Homeobox Protein PITX2
D020413:3' Untranslated Regions; D003598:Cytoskeletal Proteins; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; D000097577:Homeobox Protein PITX2; C495267:CTNNB1 protein, mouse