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PMID: 11124802 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

TGF-beta inhibits p70 S6 kinase via protein phosphatase 2A to induce G(1) arrest.

Genes & development ·Vol. 14 ·No. 24 ·2000-12-15 ·Pages 3093-101

Petritsch C, Beug H, Balmain A, Oft M

Abstract

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.

MeSH Terms
Activin Receptors, Type I Androstadienes/pharmacology Animals Cells, Cultured Chromones/pharmacology DNA-Binding Proteins/genetics,metabolism Dose-Response Relationship, Drug Enzyme Inhibitors/pharmacology Epithelial Cells/drug effects,metabolism ErbB Receptors/antagonists & inhibitors,metabolism Fibroblasts/drug effects,metabolism G1 Phase/physiology Morpholines/pharmacology Mutation Phosphoprotein Phosphatases/metabolism Phosphorylation Protein Biosynthesis Protein Phosphatase 2 Protein Serine-Threonine Kinases/genetics,metabolism Quinazolines/pharmacology Receptor, Transforming Growth Factor-beta Type I Receptor, Transforming Growth Factor-beta Type II Receptors, Transforming Growth Factor beta/genetics,metabolism Ribosomal Protein S6 Kinases/drug effects,genetics,metabolism S Phase/physiology Signal Transduction Sirolimus/pharmacology Smad2 Protein Trans-Activators/genetics,metabolism Transforming Growth Factor beta/metabolism,pharmacology Wortmannin
Chemicals
Androstadienes Chromones DNA-Binding Proteins Enzyme Inhibitors Morpholines Quinazolines Receptors, Transforming Growth Factor beta Smad2 Protein Trans-Activators Transforming Growth Factor beta 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one ErbB Receptors Protein Serine-Threonine Kinases Ribosomal Protein S6 Kinases Activin Receptors, Type I Receptor, Transforming Growth Factor-beta Type I Receptor, Transforming Growth Factor-beta Type II Phosphoprotein Phosphatases Protein Phosphatase 2 4-((3-bromophenyl)amino)-6,7-dimethoxyquinazoline Sirolimus Wortmannin
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Petritsch C
IMP, Research Institute for Molecular Pathology, A-1030 Vienna, Austria.
Beug H
Balmain A
Oft M
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36 references, click to expand
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Article Info
Journal
Genes & development
Abbr.
Genes Dev
ISSN
0890-9369
DOI
10.1101/gad.854200
Published
2000-12-15
Pages
3093-101
Language
English
Region
United States
NLM ID
8711660
PMCID
PMC317138
Subset
IM
External Links
PubMed source DOI: 10.1101/gad.854200 PMC Full Text View journal details
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