title: Transduction of growth or mitogenic signals into translational activation of TOP mRNAs is fully reliant on the phosphatidylinositol 3-kinase-mediated pathway but requires neither S6K1 nor rpS6 phosphorylation.
abstract: Translation of terminal oligopyrimidine tract (TOP) mRNAs, which encode multiple components of the protein synthesis machinery, is known to be controlled by mitogenic stimuli. We now show that the ability of cells to progress through the cell cycle is not a prerequisite for this mode of regulation. TOP mRNAs can be translationally activated when PC12 or embryonic stem (ES) cells are induced to grow (increase their size) by nerve growth factor and retinoic acid, respectively, while remaining mitotically arrested. However, both growth and mitogenic signals converge via the phosphatidylinositol 3-kinase (PI3-kinase)-mediated pathway and are transduced to efficiently translate TOP mRNAs. Translational activation of TOP mRNAs can be abolished by LY294002, a PI3-kinase inhibitor, or by overexpression of PTEN as well as by dominant-negative mutants of PI3-kinase or its effectors, PDK1 and protein kinase Balpha (PKBalpha). Likewise, overexpression of constitutively active PI3-kinase or PKBalpha can relieve the translational repression of TOP mRNAs in quiescent cells. Both mitogenic and growth signals lead to phosphorylation of ribosomal protein S6 (rpS6), which precedes the translational activation of TOP mRNAs. Nevertheless, neither rpS6 phosphorylation nor its kinase, S6K1, is essential for the translational response of these mRNAs. Thus, TOP mRNAs can be translationally activated by growth or mitogenic stimuli of ES cells, whose rpS6 is constitutively unphosphorylated due to the disruption of both alleles of S6K1. Similarly, complete inhibition of mammalian target of rapamycin (mTOR) and its effector S6K by rapamycin in various cell lines has only a mild repressive effect on the translation of TOP mRNAs. It therefore appears that translation of TOP mRNAs is primarily regulated by growth and mitogenic cues through the PI3-kinase pathway, with a minor role, if any, for the mTOR pathway.
authors.affiliation: Department of Biochemistry, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors.forename: Miri
authors.initials: M
authors.lastname: Stolovich
authors.forename: Hua
authors.initials: H
authors.lastname: Tang
authors.forename: Eran
authors.initials: E
authors.lastname: Hornstein
authors.forename: Galit
authors.initials: G
authors.lastname: Levy
authors.forename: Ruth
authors.initials: R
authors.lastname: Cohen
authors.forename: Sun Sik
authors.initials: SS
authors.lastname: Bae
authors.forename: Morris J
authors.initials: MJ
authors.lastname: Birnbaum
authors.forename: Oded
authors.initials: O
authors.lastname: Meyuhas
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000502:physiology*; D002455:Cell Division; D002460:Cell Line; D002867:Chromones / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009025:Morpholines / Q000378:metabolism; D020932:Nerve Growth Factor / Q000378:metabolism; D020648:Peptide Elongation Factor 1 / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D038601:Ribosomal Protein S6 / Q000235:genetics / Q000378:metabolism*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics / Q000378:metabolism*; D020123:Sirolimus / Q000378:metabolism; D014212:Tretinoin / Q000378:metabolism
chemical_list: D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D020932:Nerve Growth Factor; D020648:Peptide Elongation Factor 1; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D038601:Ribosomal Protein S6; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D020123:Sirolimus; D014212:Tretinoin; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C069329:RPS6KA1 protein, human; C512964:Rps6ka1 protein, mouse; C512963:Rps6ka1 protein, rat