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Updated: Oct 10, 2026

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Published on: October 27, 2020

Disruption of TGF-beta growth inhibition by oncogenic ras is linked to p27Kip1 mislocalization

X Liu1, Y Sun, M Ehrlich

  • 1Whitehead Institute for Biomedical Research, Nine Cambridge Center, Massachusetts 02142, USA.

Oncogene
|December 29, 2000
PubMed

Insights

Oncogenic Ras disrupts transforming growth factor-beta (TGF-beta) tumor suppression by mislocalizing p27KiP1 (p27) and CDK6, preventing CDK2 inhibition. Restoring Ras function normalizes these proteins and TGF-beta

Area of Science:

  • Cell Biology
  • Cancer Biology
  • Molecular Oncology

Background:

  • Oncogenic Ras expression in epithelial tumors correlates with loss of TGF-beta's anti-proliferative effects.
  • This loss was hypothesized to stem from inhibited Smad2/3 nuclear translocation.

Purpose of the Study:

  • To investigate the mechanism by which oncogenic Ras disrupts TGF-beta-mediated growth inhibition in epithelial cells.
  • To determine the role of p27KiP1 (p27) and cyclin-dependent kinases (CDKs) in this process.

Main Methods:

  • Utilized epithelial cell lines expressing oncogenic N-RasK61.
  • Assessed TGF-beta-induced Smad2/3 nuclear translocation and transcriptional activity.
  • Analyzed the subcellular localization of p27 and CDK CDK6/CDK2.
  • Evaluated the effect of Ras inactivation on TGF-beta signaling and cell growth.

Main Results:

  • Oncogenic Ras did not affect TGF-beta-induced Smad2/3 nuclear translocation or transcriptional activity.
  • Oncogenic Ras caused the mislocalization of p27 and CDK6 from the nucleus to the cytoplasm.
  • Oncogenic Ras blocked TGF-beta's ability to release p27 from CDK6, enhance p27-CDK2 binding, and inhibit CDK2 activity.
  • Inactivating Ras restored TGF-beta's growth inhibitory response and normalized p27/CDK6 localization.

Conclusions:

  • Oncogenic Ras disrupts TGF-beta-mediated growth inhibition by preventing CDK2 inactivation.
  • This occurs due to p27 and CDK2 sequestration in different cellular compartments, hindering p27's partner switching from CDK6 to CDK2.
  • Targeting Ras signaling may restore TGF-beta sensitivity in epithelial tumors.

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