p27Kip1, a cyclin-Cdk inhibitor, links transforming growth factor-beta and contact inhibition to cell cycle arrest.

TLDR

Cell‑cell contact and TGF‑β arrest G1 by raising the cyclin E threshold required for Cdk2 activation through an inhibitor that binds cyclin E‑Cdk2 complexes, a mechanism that is absent in proliferating cells where p27 is sequestered. A 27‑kDa protein that binds and prevents activation of cyclin E‑Cdk2 complexes was purified from arrested cells by cyclin E‑Cdk2 affinity chromatography, but not from proliferating cells. Cyclin D2‑Cdk4 complexes competitively bind p27, down‑regulating its activity and potentially reversing Cdk2 inhibition to permit G1 progression.

Abstract

Cell-cell contact and TGF-beta can arrest the cell cycle in G1. Mv1Lu mink epithelial cells arrested by either mechanism are incapable of assembling active complexes containing the G1 cyclin, cyclin E, and its catalytic subunit, Cdk2. These growth inhibitory signals block Cdk2 activation by raising the threshold level of cyclin E necessary to activate Cdk2. In arrested cells the threshold is set higher than physiological cyclin E levels and is determined by an inhibitor that binds to cyclin E-Cdk2 complexes. A 27-kD protein that binds to and prevents the activation of cyclin E-Cdk2 complexes can be purified from arrested cells but not from proliferating cells, using cyclin E-Cdk2 affinity chromatography. p27 is present in proliferating cells, but it is sequestered and unavailable to interact with cyclin E-Cdk2 complexes. Cyclin D2-Cdk4 complexes bind competitively to and down-regulate the activity of p27 and may thereby act in a pathway that reverses Cdk2 inhibition and enables G1 progression.