TGF-beta inhibits p70 S6 kinase via protein phosphatase 2A to induce G(1) arrest.
On TGF-beta binding, the TGF-beta receptor directly phosphorylates and activates the transcription factors Smad2/3, leading to G(1) arrest. Here, we present evidence for a second, parallel, TGF-beta-dependent pathway for cell cycle arrest, achieved via inhibition of p70(s6k). TGF-beta induces association of its receptor with protein phosphatase-2A (PP2A)-Balpha. Concomitantly, three PP2A-subunits, Balpha, Abeta, and Calpha, associate with p70(s6k), leading to its dephosphorylation and inactivation. Although either pathway is sufficient to induce G(1) arrest, abrogation of both, the inhibition of p70(s6k), and transcription through Smad proteins is required for release of epithelial cells from TGF-beta-induced G(1) arrest. TGF-beta thereby modulates the translational and posttranscriptional control of cell cycle progression.
Petritsch
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IMP, Research Institute for Molecular Pathology, A-1030 Vienna, Austria.
Beug
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Balmain
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Oft
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D030201:Activin Receptors, Type I; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D016193:G1 Phase / Q000502:physiology*; D009025:Morpholines / Q000494:pharmacology; D009154:Mutation; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D010766:Phosphorylation; D014176:Protein Biosynthesis; D054648:Protein Phosphatase 2; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D016196:S Phase / Q000502:physiology; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D051899:Smad2 Protein; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology; D000077191:Wortmannin
D000730:Androstadienes; D002867:Chromones; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D009025:Morpholines; D011799:Quinazolines; D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D066246:ErbB Receptors; D017346:Protein Serine-Threonine Kinases; D019893:Ribosomal Protein S6 Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; C088860:4-((3-bromophenyl)amino)-6,7-dimethoxyquinazoline; D020123:Sirolimus; D000077191:Wortmannin