Blog
About

  • Record: found
  • Abstract: found
  • Article: not found

The IGF-1/PI3K/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FOXO transcription factors.

Molecular Cell

genetics, Cell Line, Denervation, adverse effects, Dexamethasone, pharmacology, Forkhead Transcription Factors, Glucocorticoids, Insulin-Like Growth Factor I, metabolism, Mice, Muscle Fibers, Skeletal, drug effects, Muscle Proteins, Muscle, Skeletal, growth & development, pathology, Muscular Atrophy, chemically induced, Animals, Mutation, Phosphatidylinositol 3-Kinases, Phosphorylation, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-akt, RNA, Messenger, SKP Cullin F-Box Protein Ligases, Signal Transduction, Transcription Factors, antagonists & inhibitors, Ubiquitin-Protein Ligases, Up-Regulation

Read this article at

ScienceOpenPubMed
Bookmark
      There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

      Abstract

      Skeletal muscle size depends upon a dynamic balance between anabolic (or hypertrophic) and catabolic (or atrophic) processes. Previously, no link between the molecular mediators of atrophy and hypertrophy had been reported. We demonstrate a hierarchy between the signals which mediate hypertrophy and those which mediate atrophy: the IGF-1/PI3K/Akt pathway, which has been shown to induce hypertrophy, prevents induction of requisite atrophy mediators, namely the muscle-specific ubiquitin ligases MAFbx and MuRF1. Moreover, the mechanism for this inhibition involves Akt-mediated inhibition of the FoxO family of transcription factors; a mutant form of FOXO1, which prevents Akt phosphorylation, thereby prevents Akt-mediated inhibition of MuRF1 and MAFbx upregulation. Our study thus defines a previously uncharacterized function for Akt, which has important therapeutic relevance: Akt is not only capable of activating prosynthetic pathways, as previously demonstrated, but is simultaneously and dominantly able to suppress catabolic pathways, allowing it to prevent glucocorticoid and denervation-induced muscle atrophy.

      Related collections

      Most cited references 28

      • Record: found
      • Abstract: not found
      • Article: not found

      The phosphatidylinositol 3-Kinase AKT pathway in human cancer.

        Bookmark
        • Record: found
        • Abstract: found
        • Article: not found

        Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor.

         A Bonni,  L. Hu,  Jean Lin (1999)
        Survival factors can suppress apoptosis in a transcription-independent manner by activating the serine/ threonine kinase Akt, which then phosphorylates and inactivates components of the apoptotic machinery, including BAD and Caspase 9. In this study, we demonstrate that Akt also regulates the activity of FKHRL1, a member of the Forkhead family of transcription factors. In the presence of survival factors, Akt phosphorylates FKHRL1, leading to FKHRL1's association with 14-3-3 proteins and FKHRL1's retention in the cytoplasm. Survival factor withdrawal leads to FKHRL1 dephosphorylation, nuclear translocation, and target gene activation. Within the nucleus, FKHRL1 triggers apoptosis most likely by inducing the expression of genes that are critical for cell death, such as the Fas ligand gene.
          Bookmark
          • Record: found
          • Abstract: found
          • Article: not found

          The phosphoinositide 3-kinase pathway.

           Lewis Cantley (2002)
          Phosphorylated lipids are produced at cellular membranes during signaling events and contribute to the recruitment and activation of various signaling components. The role of phosphoinositide 3-kinase (PI3K), which catalyzes the production of phosphatidylinositol-3,4,5-trisphosphate, in cell survival pathways; the regulation of gene expression and cell metabolism; and cytoskeletal rearrangements are highlighted. The PI3K pathway is implicated in human diseases including diabetes and cancer, and understanding the intricacies of this pathway may provide new avenues for therapuetic intervention.
            Bookmark

            Author and article information

            Journal
            15125842

            Comments

            Comment on this article