The Wnt/beta-catenin-->Pitx2 pathway controls the turnover of Pitx2 and other unstable mRNAs

Mol Cell. 2003 Nov;12(5):1201-11. doi: 10.1016/s1097-2765(03)00407-6.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Animals
  • Cell Line
  • Cytoskeletal Proteins / metabolism*
  • Gene Expression Regulation*
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Mice
  • Nuclear Proteins*
  • Open Reading Frames
  • Proto-Oncogene Proteins / metabolism*
  • RNA Stability
  • RNA, Messenger / metabolism*
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Trans-Activators / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription, Genetic
  • Wnt Proteins
  • Zebrafish Proteins*
  • beta Catenin

Substances

  • 3' Untranslated Regions
  • CTNNB1 protein, mouse
  • Cytoskeletal Proteins
  • Homeodomain Proteins
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Recombinant Fusion Proteins
  • Trans-Activators
  • Transcription Factors
  • Wnt Proteins
  • Zebrafish Proteins
  • beta Catenin
  • homeobox protein PITX2