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Vol. 14, No. 24, pp. 3093-3101, December 15, 2000
inhibits p70 S6 kinase via protein phosphatase 2A to induce G1 arrest
1 IMP, Research Institute for Molecular Pathology, A-1030
Vienna, Austria; 2 University of California San Francisco
Cancer Center, San Francisco, California 94143, USA, and Onyx
Pharmaceuticals, Richmond, California 94801, USA
On TGF-
binding, the TGF- receptor directly phosphorylates
and activates the transcription factors Smad2/3, leading to
G1 arrest. Here, we present evidence for a second, parallel,
TGF--dependent pathway for cell cycle arrest, achieved via
inhibition of p70s6k. TGF- induces association of its
receptor with protein phosphatase-2A (PP2A)-B
. Concomitantly, three
PP2A-subunits, B, A, and C, associate with p70s6k,
leading to its dephosphorylation and inactivation. Although either
pathway is sufficient to induce G1 arrest, abrogation of both, the inhibition of p70s6k, and transcription through
Smad proteins is required for release of epithelial cells from
TGF--induced G1 arrest. TGF- thereby modulates the
translational and posttranscriptional control of cell cycle progression.
[Key Words:
TGF- p70s6k; PP2A; G1
arrest; cell cycle]
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