Blockade of TCFβ3 up-regulation of p27Kip1 and p21(ip1 by expression of RasN17 in epithelial cells

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journalpeer-review

35 Scopus Citations
View graph of relations

Author(s)

Detail(s)

Original languageEnglish
Pages (from-to)47-55
Journal / PublicationOncogene
Volume17
Issue number1
Publication statusPublished - 9 Jul 1998
Externally publishedYes

Abstract

Our previous data demonstrated that Ras activation is necessary and sufficient for transforming growth factor β (TGFβ)-mediated Erk1 activation, and is partially required for the inhibition of cyclin-dependent kinase 2 (Cdk2) activity, cyclin A expression and DNA synthesis by TGFβ (KM Mulder and SL Morris, J. Biol. Chem., 267: 5029 ± 5031, 1992; MT Hartsough and KM MulderJ. Biol. Chem., 270: 7117 ± 7124, 1995; and MT Hartsough et al., J. Biol. Chem., 271: 22368 ± 22375, 1996). Here, we examined the kinetics and role of Ras in TGFβ3-mediated effects on specific G1 cell cycle components in TGFβ-sensitive (4-1) acid TGFβ-resistant (4-6) intestinal epithelial cells (IEC's). Our results indicate that inactivation of Ras by stable, inducible expression of a dominant-negative mutant of Ras (RasN17) completely abrogated the ability of TGFβ3 to up-regulate both CKI's. In contrast, the ability of TGFβ3 to up-regulate p27Kip1 and p21Cip1 was maintained in ZnCl2-treated control cells. Inactivation of Ras also completely blocked the rapid TGFβ-mediated increase in new synthesis of p27Kip1 protein. Moreover, up-regulation of p21Cip1 protein levels and new synthesis of p27Kip1, as well as the association of these CKI's with Cdk2, preceded the decrease in Cdk2 activity by TGFβ. Collectively, our results suggest that p21Cip1 and p27Kip1 are upstream effecters of the TGFβ-mediated inhibition of Cdk2 activity in IEC 4-1 cells, and demonstrate that Ras activation is obligatory for TGFβ-mediated up-regulation of these CKIs in untransformed epithelial cells.

Research Area(s)

  • Cell cycle, Intestinal epithial cells, p21(Cip1), p27(Kip1), Ras, TGFβ