Akt2-mediated phosphorylation of Pitx2 controls Ccnd1 mRNA decay during muscle cell differentiation

R. Gherzi, M. Trabucchi, M. Ponassi, Imed Gallouzi, M. G. Rosenfeld, P. Briata

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Paired-like homeodomain 2 (Pitx2), first identified as the gene responsible for the Axenfeld-Rieger syndrome, encodes a protein factor that, controlling cell proliferation in a tissue-specific manner, has a crucial role in morphogenesis. During embryonic development, Pitx2 exerts a role in the expansion of muscle progenitors and is expressed at all stages of myogenic progression. In this study, we show that Pitx2 is phosphorylated by the protein kinase Akt2 and is necessary to ensure proper C2C12 myoblast proliferation and differentiation. Pitx2 associates with a ribonucleoprotein complex that includes the mRNA stabilizing factor HuR and sustains Ccnd1 (also known as Cyclin D1) expression, thereby prolonging its mRNA half-life. When the differentiation program is initiated, phosphorylation by Akt2 impairs the ability of Pitx2 to associate with the Ccnd1 mRNA-stabilizing complex that includes HuR and, as a consequence, Ccnd1 mRNA half-life is shortened. We propose that unphosphorylated Pitx2 is required to favor HuR-mediated Ccnd1 mRNA stabilization, thus sustaining myoblast proliferation. Upon Akt2-phosphorylation, the complex Pitx2/HuR/Ccnd1 mRNA dissociates and Ccnd1 mRNA is destabilized. These events contribute to the switch of C2C12 cells from a proliferating to a differentiating phenotype.

Original languageEnglish
Pages (from-to)975-983
Number of pages9
JournalCell Death and Differentiation
Volume17
Issue number6
DOIs
Publication statusPublished - Jun 2010
Externally publishedYes

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Keywords

  • Akt2
  • HuR
  • mRNA decay
  • Myoblasts
  • Pitx2

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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