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TGF-beta inhibits p70 S6 kinase via protein phosphatase 2A to induce G(1) arrest
C Petritsch1, H Beug, A Balmain
1IMP, Research Institute for Molecular Pathology, A-1030 Vienna, Austria.
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.
Insights
Transforming growth factor-beta (TGF-beta) triggers cell cycle arrest through two pathways: Smad activation and p70 S6 kinase (p70(s6k)) inhibition. Both pathways are necessary to release epithelial cells from TGF-beta-induced arrest.
Area of Science:
- Cell Biology
- Molecular Biology
- Signal Transduction
Background:
- Transforming growth factor-beta (TGF-beta) is a key regulator of cell proliferation and differentiation.
- TGF-beta signaling pathways are complex and involve multiple downstream effectors.
- Understanding these pathways is crucial for comprehending cell cycle control and cancer development.
Purpose of the Study:
- To elucidate the mechanisms by which TGF-beta induces G(1) cell cycle arrest.
- To identify parallel TGF-beta-dependent pathways regulating cell cycle progression.
- To investigate the roles of Smad proteins and p70 S6 kinase (p70(s6k)) in TGF-beta-mediated cell cycle control.
Main Methods:
- Investigated TGF-beta receptor interactions with downstream signaling molecules.
- Utilized biochemical assays to assess protein phosphorylation and dephosphorylation.
- Examined the association of protein phosphatase-2A (PP2A) subunits with p70(s6k).
- Analyzed the requirement of Smad proteins and p70(s6k) inhibition for cell cycle release.
Main Results:
- TGF-beta receptor activation leads to Smad2/3 phosphorylation and G(1) arrest.
- A parallel pathway involves TGF-beta receptor association with PP2A-Balpha, leading to p70(s6k) dephosphorylation and inactivation.
- Both Smad-dependent and p70(s6k) inhibition pathways are required for epithelial cells to exit TGF-beta-induced G(1) arrest.
- TGF-beta modulates both translational and posttranscriptional control of cell cycle progression.
Conclusions:
- TGF-beta utilizes two distinct but cooperative pathways to enforce G(1) cell cycle arrest.
- The interplay between Smad signaling and PP2A/p70(s6k) pathway is critical for cell cycle regulation by TGF-beta.
- These findings reveal a comprehensive model of TGF-beta's role in cell cycle control, impacting translational and posttranscriptional mechanisms.