FOXP1 acts through a negative feedback loop to suppress FOXO-induced apoptosis

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• Título: FOXP1 acts through a negative feedback loop to suppress FOXO-induced apoptosis
• Autor: Gómez Puerto, María Catalina; Boxtel, R van; Mokry, M; Eijkelenboom, A; Vos, Kristan E van der; Nieuwenhuis, E E; Burgering, BM; Lam, E. W; Coffer, Paul J
• Publicación original: Cell Death and Differentiation; Vol. 20, 2013
• Descripción física: PDF
• Nota general:
  • Transcriptional activity of Forkhead box transcription factor class O (FOXO) proteins can result in a variety of cellular outcomes depending on cell type and activating stimulus. These transcription factors are negatively regulated by the phosphoinositol 3-kinase (PI3K)–protein kinase B (PKB) signaling pathway, which is thought to have a pivotal role in regulating survival of tumor cells in a variety of cancers.
    Recently, it has become clear that FOXO proteins can promote resistance to anti-cancer therapeutics, designed to inhibit PI3K–PKB activity, by inducing the expression of proteins that provide feedback at different levels of this pathway. We questioned whether such a feedback mechanism may also exist directly at the level of FOXO-induced transcription.
    To identify critical modulators of FOXO transcriptional output, we performed gene expression analyses after conditional activation of key components of the PI3K–PKB–FOXO signaling pathway and identified FOXP1 as a direct FOXO transcriptional target. Using chromatin immunoprecipitation followed by next-generation sequencing, we show that FOXP1 binds enhancers that are pre-occupied by FOXO3.
    By sequencing the transcriptomes of cells in which FOXO is specifically activated in the absence of FOXP1, we demonstrate that FOXP1 can modulate the expression of a specific subset of FOXO target genes, including inhibiting expression of the pro-apoptotic gene BIK. FOXO activation in FOXP1-knockdown cells resulted in increased cell death, demonstrating that FOXP1 prevents FOXO-induced apoptosis. We therefore propose that FOXP1 represents an important modulator of FOXO-induced transcription, promoting cellular survival.
• Notas de reproducción original: Digitalización realizada por la Biblioteca Virtual del Banco de la República (Colombia)
• Notas:
  • Resumen: FOXO; FOXP1; Transcriptional activity; Enhancer occupancy; Cell fate outcome; apoptosis
  • © Derechos reservados del autor
  • Colfuturo
• Forma/género: texto
• Idioma: inglés
• Institución origen: Biblioteca Virtual del Banco de la República
• Encabezamiento de materia:
  • Ciencias naturales y matemáticas; Ciencias naturales y matemáticas / Ciencias de la vida Biología; Tecnología; Tecnología / Ciencias médicas Medicina