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Updated: Aug 11, 2026

Analysis of Cell Cycle Position in Mammalian Cells
12:19

Analysis of Cell Cycle Position in Mammalian Cells

Published on: January 21, 2012

PAK is essential for RAS-induced upregulation of cyclin D1 during the G1 to S transition

Thao Nheu1, Hong He, Yumiko Hirokawa

  • 1Ludwig Institute for Cancer Research, Parkville/Melbourne, Australia.

Cell Cycle (Georgetown, Tex.)
|December 6, 2003
PubMed

Insights

Oncogenic RAS proteins drive cancer by promoting cell cycle progression. This study reveals that PAK1-3 kinases are crucial for RAS-induced cyclin D1 upregulation, selectively inhibiting malignant cell growth.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • Oncogenic RAS mutants promote cell cycle progression, specifically the G1 to S transition.
  • This is achieved by upregulating cyclin D1 and downregulating p27, a cyclin-dependent kinase inhibitor.
  • Phosphoinositide 3-kinase (PI-3 kinase) is implicated in regulating both cyclin D1 and p27.

Purpose of the Study:

  • To investigate the role of PAK1-3 kinases in RAS-induced cell cycle progression.
  • To determine if PAK1-3 kinases mediate the upregulation of cyclin D1 and downregulation of p27.
  • To evaluate the therapeutic potential of PAK1-3 inhibitors in RAS-driven cancers.

Main Methods:

  • Utilized two distinct inhibitors specific for PAK1-3 (CEP-1347 and WR-PAK18).
  • Investigated the effects of these inhibitors on RAS-transformed cells and normal cells.
  • Examined the impact on cyclin D1 and p27 levels and cell cycle progression.

Main Results:

  • PAK1-3 kinases, acting downstream of PI-3 kinase and upstream of the Raf/MEK/ERKs cascade, are essential for RAS-induced cyclin D1 upregulation.
  • PAK1-3 kinases do not appear to be involved in the RAS-induced downregulation of p27.
  • PAK-inhibitors selectively blocked malignant growth in RAS transformants with constitutively activated PAK1, but not normal cell growth.

Conclusions:

  • RAS-induced cell cycle progression relies on PAK1-3 kinases for cyclin D1 upregulation.
  • RAS-transformed cells are dependent on high PAK1 levels for entry into the S phase.
  • PAK1-3 kinases represent a potential therapeutic target for RAS-driven cancers.

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