p21Cip1 and p27Kip1 Act in Synergy to Alter the Sensitivity of Naive T Cells to TGF-β-Mediated G1 Arrest through Modulation of IL-2 Responsiveness

Abstract

Induction of G1 arrest by TGF-β correlates with the regulation of p21Cip1 and p27Kip1, members of the Cip/Kip family of cyclin-dependent kinase inhibitors (cki). However, no definitive evidence exists that these proteins play a causal role in TGF-β1-induced growth arrest in lymphocytes. In this report we show the suppression of cell cycle progression by TGF-β is diminished in T cells from mice deficient for both p21Cip1 and p27Kip1 (double-knockout (DKO)) only when activated under conditions of optimal costimulation. Although there is an IL-2-dependent enhanced proliferation of CD8+ T cells from DKO mice, TGF-β is able to maximally suppress the proliferation of DKO T cells when activated under conditions of low costimulatory strength. We also show that the induction of p15Ink4b in T cells stimulated in the presence of TGF-β is not essential, as TGF-β also efficiently suppressed proliferation of T cells from p15Ink4b−/− mice. Finally, although these cki are dispensable for the suppression of T cell proliferation by TGF-β, we now describe a Smad3-dependent down-regulation of cdk4, suggesting a potential mechanism underlying to resistance of Smad3−/− T cells to the induction of growth arrest by TGF-β. In summary, the growth suppressive effects of TGF-β in naive T cells are a function of the strength of costimulation, and alterations in the expression of cki modify the sensitivity to TGF-β by lowering thresholds for a maximal mitogenic response.

Epigallocatechin-3-gallate induces apoptosis and cell cycle arrest in HTLV-1-positive and -negative leukemia cells

“…Contrary to this results are the findings by Inman and Allday [33] which showed that TGF-b was associated with cleavage of PARP, a DNA repair enzyme but with no change in the levels of Bcl-2, an antiapoptotic protein. The inhibition of proliferation is at the G 1 phase of the cell cycle through p21, which are in agreement with the results obtained in this study [34].…”

“…For TGF-b to function properly, expression of p53 is crucial. On the other hand, p21 over-expression increased sensitivity of T-cells to TGF-b [34]. Lack of proper levels of p53 involves a defective cytostatic response to TGF-b and the incapability to switch on the expression of the CDK inhibitor, p21 [42].…”

Lineage and signal strength determine the inhibitory effect of transforming growth factor β1 (TGF-β1) on human antigen-specific Th1 and Th2 memory cells

“…Cell cycle arrest induced by TGF-b1 in the G1 phase is mediated by up regulation of cell-cycle inhibitors p21 and p27 and down regulation of CDK4 [6]. Recently it could be demonstrated that suppression of cell cycle progression by TGF-b1 is reduced in T cells from mice deficient for both p21 and p27 only when activated under conditions of optimal costimulation, however, TGF-b1 seemed to be able to maximally suppress the proliferation of these T cells when activated under conditions of low costimulatory strength [26]. Our finding suggests that the mechanism by which proliferation and entry into the cell cycle is inhibited upon exposure to TGF-b1 can be overcome with adequate stimulation via the TCR.…”

Transforming growth factor-β in cancer and metastasis

“…Induction of p15 Ink4b by TGF-β in astrocytes is dependent on functional Smads and is dramatically altered in human glioma cell lines [137]. In transgenic mice that are deficient for both p21 Cip1 and p27 Kip1 , suppression of cell cycle progression is diminished in T-cells when activated under conditions of optimal co-stimulation [189]. TGF-β is able to maximally suppress the proliferation of T-cells from p21 Cip1 and p27 Kip1 double null transgenic mice when it is activated under conditions of low co-stimulatory strength.…”