Blockade of TCFβ3 up-regulation of p27(Kip1) and p21(Cip1) by expression of RasN17 in epithelial cells

Jianbo Yue, Annie Buard, Kathleen Mulder

Research output: Contribution to journalArticle

36 Citations (Scopus)

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. 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 p27(Kip1) and p21(Cip1) was maintained in ZnCl2-treated control cells. Inactivation of Ras also completely blocked the rapid TGFβ-mediated increase in new synthesis of p27(K)ip1) protein. Moreover, up-regulation of p21(Cip1) protein levels and new synthesis of p27(Kip1), as well as the association of these CKI's with Cdk2, preceded the decrease in Cdk2 activity by TGFβ. Collectively, our results suggest that p21(Cip1) and p27(Kip1) 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.

Original languageEnglish (US)
Pages (from-to)47-55
Number of pages9
JournalOncogene
Volume17
Issue number1
DOIs
StatePublished - Jul 9 1998

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Transforming Growth Factors
Up-Regulation
Epithelial Cells
Cyclin-Dependent Kinase 2
Cyclin A
Cellular Structures
Cell Cycle
Acids
DNA

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

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title = "Blockade of TCFβ3 up-regulation of p27(Kip1) and p21(Cip1) by expression of RasN17 in epithelial cells",
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. 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 p27(Kip1) and p21(Cip1) was maintained in ZnCl2-treated control cells. Inactivation of Ras also completely blocked the rapid TGFβ-mediated increase in new synthesis of p27(K)ip1) protein. Moreover, up-regulation of p21(Cip1) protein levels and new synthesis of p27(Kip1), as well as the association of these CKI's with Cdk2, preceded the decrease in Cdk2 activity by TGFβ. Collectively, our results suggest that p21(Cip1) and p27(Kip1) 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.",
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Blockade of TCFβ3 up-regulation of p27(Kip1) and p21(Cip1) by expression of RasN17 in epithelial cells. / Yue, Jianbo; Buard, Annie; Mulder, Kathleen.

In: Oncogene, Vol. 17, No. 1, 09.07.1998, p. 47-55.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Blockade of TCFβ3 up-regulation of p27(Kip1) and p21(Cip1) by expression of RasN17 in epithelial cells

AU - Yue, Jianbo

AU - Buard, Annie

AU - Mulder, Kathleen

PY - 1998/7/9

Y1 - 1998/7/9

N2 - 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. 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 p27(Kip1) and p21(Cip1) was maintained in ZnCl2-treated control cells. Inactivation of Ras also completely blocked the rapid TGFβ-mediated increase in new synthesis of p27(K)ip1) protein. Moreover, up-regulation of p21(Cip1) protein levels and new synthesis of p27(Kip1), as well as the association of these CKI's with Cdk2, preceded the decrease in Cdk2 activity by TGFβ. Collectively, our results suggest that p21(Cip1) and p27(Kip1) 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.

AB - 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. 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 p27(Kip1) and p21(Cip1) was maintained in ZnCl2-treated control cells. Inactivation of Ras also completely blocked the rapid TGFβ-mediated increase in new synthesis of p27(K)ip1) protein. Moreover, up-regulation of p21(Cip1) protein levels and new synthesis of p27(Kip1), as well as the association of these CKI's with Cdk2, preceded the decrease in Cdk2 activity by TGFβ. Collectively, our results suggest that p21(Cip1) and p27(Kip1) 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.

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