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p27kip1 controls H-Ras/MAPK activation and cell cycle entry via modulation of MT stability

Linda Fabris1, Stefania Berton1, Ilenia Pellizzari1

  • 1Division of Experimental Oncology 2, Department of Translational Research, Centro di Riferimento Oncologico (CRO Aviano), National Cancer Institute, 33081 Aviano, Italy;

Proceedings of the National Academy of Sciences of the United States of America
|October 30, 2015
PubMed

Insights

The cell cycle regulator p27(kip1) controls cell proliferation by stabilizing microtubules and influencing Ras-MAPK signaling. Deleting stathmin impairs p27(kip1)

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • The cyclin-dependent kinase (CDK) inhibitor p27(kip1) is a key regulator of cell cycle progression and microtubule (MT) stability.
  • p27(kip1) modulates MT stability via stathmin interaction and direct MT binding.
  • Previous studies suggest a CDK-independent role for p27(kip1) in cell proliferation control.

Purpose of the Study:

  • To investigate the impact of p27(kip1)-mediated MT stability on cell cycle entry and signaling pathways.
  • To elucidate the molecular mechanisms by which p27(kip1) and stathmin regulate cell proliferation.
  • To identify the role of the p27(kip1)-stathmin axis in Ras-MAPK pathway activation.

Main Methods:

  • Gene expression profiling and bioinformatic analyses.
  • Studies using p27(kip1)-null and p27(kip1)/stathmin double-knockout (KO) mouse models.
  • Analysis of H-Ras trafficking and ubiquitination levels.

Main Results:

  • Concomitant deletion of stathmin impaired faster cell cycle entry in p27(kip1)-null cells.
  • p27(kip1) and stathmin were found to jointly control MAPK pathway activation.
  • p27(kip1) regulates H-Ras trafficking and ubiquitination, thereby restraining its activation through MT stability control.

Conclusions:

  • p27(kip1) controls G1/S-phase transition via MT stability and Ras-MAPK signaling.
  • The p27(kip1)-stathmin interaction fine-tunes the spatiotemporal activation of the Ras-MAPK pathway.
  • This study reveals a novel regulatory axis impacting cell cycle progression and signaling.
Keywords:
Rascell cyclemicrotubulesp27kip1stathmin

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