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

Abstract

Cell-cell contact and TGF-13 can arrest the cell cycle in G1. MvlLu mink epithelial cells arrested by either mechanism are incapable of assembling active complexes containing the G1 cyclin, cyclin E, and its catalytic 8ubunit, 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.

SRF is a nuclear repressor of Smad3-mediated TGF-β signaling

“…This effect is mediated by several events that are activated downstream of the TGF-b receptor. This includes the transcriptional repression of the proto-oncogene c-myc (Alexandrow et al, 1995), downmodulation of the expression and activities of G1 and G2 CDK and cyclins (Ewen et al, 1993;Geng and Weinberg, 1993;Iavarone and Massague, 1997), and activation of the genes encoding p15 INK4b (Hannon and Beach, 1994), p21 Cip1 (Datto et al, 1995;Claassen and Hann, 2000) and p27 Kip1 (Polyak et al, 1994;Depoortere et al, 2000) that encode CDK inhibitors. Previously, it was demonstrated that Smads functionally cooperate with Sp1 to activate the human p21 Cip1 and p15 INK4b promoters.…”

BPV-4 E8 transforms NIH3T3 cells, up-regulates cyclin A and cyclin A-associated kinase activity and de-regulates expression of the cdk inhibitor p27Kip1

“…Proliferation of these cells is likely to be restricted by TGF-b, a known modulator of p27 Kip1 function (Polyak et al, 1994). E8 expression may extend the proliferative capacity of host cells by blocking TGF-b mediated inhibition of cell proliferation, through abrogation of p27 Kip1 function, and so promote progression to cancer.…”

Pretreatment with transforming growth factor beta-3 protects small intestinal stem cells against radiation damage in vivo

“…TGF-,3 acts, at least in part, through inhibition of cdk-/cyclin-dependent kinase activity during the GI phase of the cell cycle (Polyak et al, 1994;Sherr and Roberts 1995). We have recently shown that TGF-,B1 administered over a protracted period of time can significantly suppress the proliferative activity in the small intestinal crypts, the effect being particularly pronounced in the stem cell region .…”

“…stimulators before or inhibitors after cytotoxic exposure, might be expected to result not in protection but sensitization of the system. TGF-js have been shown to reversibly inhibit the proliferation of epithelial and haematopoietic progenitor cells in mid-late G, phase (Polyak et al, 1994;Sherr and Roberts, 1995). Maximal inhibition of cell cycling in unsynchronized cells requires that TGF-P be present for one cell cycle period (Geng and Weinberg, 1993).…”