title: mTOR transcriptionally and post-transcriptionally regulates Npm1 gene expression to contribute to enhanced proliferation in cells with Pten inactivation.
abstract: The mammalian target of rapamycin (mTOR) plays essential roles in the regulation of growth-related processes such as protein synthesis, cell sizing and metabolism in both normal and pathological growing conditions. These functions of mTOR are thought to be largely a consequence of its cytoplasmic activity in regulating translation rate, but accumulating data highlight supplementary role(s) for this serine/threonine kinase within the nucleus. Indeed, the nuclear activities of mTOR are currently associated with the control of protein biosynthetic capacity through its ability to regulate the expression of gene products involved in the control of ribosomal biogenesis and proliferation. Using primary murine embryo fibroblasts (MEFs), we observed that cells with overactive mTOR signaling displayed higher abundance for the growth-associated Npm1 protein, in what represents a novel mechanism of Npm1 gene regulation. We show that Npm1 gene expression is dependent on mTOR as demonstrated by treatment of wild-type and Pten inactivated MEFs cultured with rapamycin or by transient transfections of small interfering RNA directed against mTOR. In accordance, the mTOR kinase localizes to the Npm1 promoter gene in vivo and it enhances the activity of a human NPM1-luciferase reporter gene providing an opportunity for direct control. Interestingly, rapamycin did not dislodge mTOR from the Npm1 promoter but rather strongly destabilized the Npm1 transcript by increasing its turnover. Using a prostate-specific Pten-deleted mouse model of cancer, Npm1 mRNA levels were found up-regulated and sensitive to rapamycin. Finally, we also showed that Npm1 is required to promote mTOR-dependent cell proliferation. We therefore proposed a model whereby mTOR is closely involved in the transcriptional and posttranscriptional regulation of Npm1 gene expression with implications in development and diseases including cancer.
authors.affiliation: a Université Clermont Auvergne, Université Blaise Pascal, GReD , BP 10448 , Clermont-Ferrand , France.|b CNRS, UMR6293, GReD , Clermont-Ferrand , France.|c Inserm, UMR1103, GReD , Clermont-Ferrand , France.
authors.forename: Rafik
authors.initials: R
authors.lastname: Boudra
authors.affiliation: a Université Clermont Auvergne, Université Blaise Pascal, GReD , BP 10448 , Clermont-Ferrand , France.|b CNRS, UMR6293, GReD , Clermont-Ferrand , France.|c Inserm, UMR1103, GReD , Clermont-Ferrand , France.
authors.forename: Rosyne
authors.initials: R
authors.lastname: Lagrafeuille
authors.affiliation: a Université Clermont Auvergne, Université Blaise Pascal, GReD , BP 10448 , Clermont-Ferrand , France.|b CNRS, UMR6293, GReD , Clermont-Ferrand , France.|c Inserm, UMR1103, GReD , Clermont-Ferrand , France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Lours-Calet
authors.affiliation: a Université Clermont Auvergne, Université Blaise Pascal, GReD , BP 10448 , Clermont-Ferrand , France.|b CNRS, UMR6293, GReD , Clermont-Ferrand , France.|c Inserm, UMR1103, GReD , Clermont-Ferrand , France.
authors.forename: Cyrille
authors.initials: C
authors.lastname: de Joussineau
authors.affiliation: a Université Clermont Auvergne, Université Blaise Pascal, GReD , BP 10448 , Clermont-Ferrand , France.|b CNRS, UMR6293, GReD , Clermont-Ferrand , France.|c Inserm, UMR1103, GReD , Clermont-Ferrand , France.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Loubeau-Legros
authors.affiliation: d Inserm U1052, CNRS UMR5286, Center de Recherche en Cancérologie de Lyon , Lyon , France.
authors.forename: Cédric
authors.initials: C
authors.lastname: Chaveroux
authors.affiliation: a Université Clermont Auvergne, Université Blaise Pascal, GReD , BP 10448 , Clermont-Ferrand , France.|b CNRS, UMR6293, GReD , Clermont-Ferrand , France.|c Inserm, UMR1103, GReD , Clermont-Ferrand , France.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Saru
authors.affiliation: a Université Clermont Auvergne, Université Blaise Pascal, GReD , BP 10448 , Clermont-Ferrand , France.|b CNRS, UMR6293, GReD , Clermont-Ferrand , France.|c Inserm, UMR1103, GReD , Clermont-Ferrand , France.
authors.forename: Silvère
authors.initials: S
authors.lastname: Baron
authors.affiliation: a Université Clermont Auvergne, Université Blaise Pascal, GReD , BP 10448 , Clermont-Ferrand , France.|b CNRS, UMR6293, GReD , Clermont-Ferrand , France.|c Inserm, UMR1103, GReD , Clermont-Ferrand , France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Morel
authors.affiliation: a Université Clermont Auvergne, Université Blaise Pascal, GReD , BP 10448 , Clermont-Ferrand , France.|b CNRS, UMR6293, GReD , Clermont-Ferrand , France.|c Inserm, UMR1103, GReD , Clermont-Ferrand , France.
authors.forename: Claude
authors.initials: C
authors.lastname: Beaudoin
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D006367:HeLa Cells; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000090243:Nucleophosmin; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014183:Transplantation, Heterologous; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C000716967:NPM1 protein, human; C000715570:Npm1 protein, mouse; D009687:Nuclear Proteins; D012333:RNA, Messenger; D000090243:Nucleophosmin; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; D020123:Sirolimus
keywords: Npm1; cell proliferation; gene expression; mTOR; prostate cancer