title: ATP-competitive mTOR kinase inhibitors delay plant growth by triggering early differentiation of meristematic cells but no developmental patterning change.
abstract: The TOR (target of rapamycin) protein, a large phosphatidylinositol 3-kinase-like protein kinase (PIKK) that is conserved in eukaryotes and is a central regulator of growth and metabolism. The analysis of function of TOR in plant growth and development has been limited by the fact that plants are very poorly sensitive to rapamycin. As the kinase domain of TOR is highly conserved, this study analysed the dose-dependent effect of three sets of first- and second-generation ATP-competitive inhibitors (called asTORis for active-site TOR inhibitors) recently developed for the human TOR kinase on Arabidopsis thaliana growth. All six asTORis inhibited plant root growth in a dose-dependent manner, with 50% growth inhibitory doses (GI50) of <10 μM and <1 μM for the first- and second-generation inhibitors, respectively, similarly to the values in mammalian cells. A genetic approach further demonstrated that only asTORis inhibited root growth in an AtTOR gene-dosage-dependent manner. AsTORis decreased the length of: (i) the meristematic zone (MZ); (ii) the division zone in the MZ; (iii) epidermal cells in the elongation zone; and (iv) root hair cells. Whereas meristematic cells committed to early differentiation, the pattern of cell differentiation was not affected per se. AsTORis-induced root hair growth phenotype was shown to be specific by using other growth inhibitors blocking the cell cycle or translation. AsTORis dose-dependent inhibition of growth and root hairs was also observed in diverse groups of flowering plants, indicating that asTORis can be used to study the TOR pathway in other angiosperms, including crop plants.
authors: Aix-Marseille Université, Laboratoire de Génétique et Biophysique des Plantes, Marseille, F-13009, France.
authors: Marie-Hélène
authors: MH
authors: Montané
authors: Benoît
authors: B
authors: Menand
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology*; D017360:Arabidopsis / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development*; D029681:Arabidopsis Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D019521:Body Patterning / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D018628:Gene Dosage; D057895:Haploinsufficiency / Q000187:drug effects; D006801:Humans; D018519:Meristem / Q000166:cytology* / Q000187:drug effects / Q000254:growth & development; D009025:Morpholines / Q000494:pharmacology; D009287:Naphthyridines / Q000494:pharmacology; D010641:Phenotype; D010671:Phenylurea Compounds / Q000494:pharmacology; D063245:Plant Development / Q000187:drug effects*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C558529:9-(6-aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo(h)(1,6)naphthyridin-2(1H)-one; D029681:Arabidopsis Proteins; D009025:Morpholines; D009287:Naphthyridines; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; C547581:WYE 125132; D000255:Adenosine Triphosphate; C546624:(5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: ATP-competitive mTOR kinase inhibitors; Arabidopsis; Lotus; Nicotiana; cell size; differentiation; meristem; millet; rice; root growth; root hairs; target of rapamycin.
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