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Spatio-Temporal Manipulation of Small GTPase Activity at Subcellular Level and on Timescale of Seconds in Living Cells
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The Rac activator Tiam1 prevents keratinocyte apoptosis by controlling ROS-mediated ERK phosphorylation

Tomasz P Rygiel1, Alexander E Mertens, Kristin Strumane

  • 1Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.

Journal of Cell Science
|March 20, 2008
PubMed

Insights

The Rac activator Tiam1 regulates skin cell apoptosis by controlling reactive oxygen species (ROS) production. Tiam1 deficiency impairs ROS generation, leading to increased apoptosis and reduced skin tumor development.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Dermatology

Background:

  • Tiam1 (T-cell lymphoma invasion and metastasis 1) is a known activator of the small GTPase Rac.
  • Previous studies showed Tiam1 knockout mice exhibit resistance to skin tumorigenesis, linked to increased keratinocyte apoptosis.
  • The precise mechanisms by which Tiam1 influences apoptosis remain to be fully elucidated.

Purpose of the Study:

  • To investigate the mechanisms underlying Tiam1's protective role against apoptosis in keratinocytes.
  • To determine the role of Tiam1-mediated Rac activation in regulating keratinocyte survival.
  • To explore the connection between Tiam1, reactive oxygen species (ROS), and apoptotic signaling pathways.

Main Methods:

  • Utilized Tiam1 knockout (KO) keratinocytes and wild-type (WT) cells.
  • Induced apoptosis using growth factor deprivation and heat-shock treatments.
  • Assessed apoptosis levels, Rac activation, ERK phosphorylation, and intracellular ROS content.
  • Investigated the role of NADPH oxidase (Nox) in Tiam1-mediated ROS production.

Main Results:

  • Tiam1-KO keratinocytes displayed heightened susceptibility to apoptosis upon various stimuli.
  • Active Tiam1 expression rescued the apoptotic phenotype, confirming the role of Tiam1-mediated Rac activation.
  • Growth factor starvation-induced apoptosis in Tiam1-KO cells correlated with reduced ERK phosphorylation and lower intracellular ROS levels.
  • Tiam1 deficiency or ROS inhibition impaired ERK phosphorylation and sensitized WT keratinocytes to apoptosis.

Conclusions:

  • Tiam1 is crucial for maintaining intracellular ROS balance in keratinocytes via Nox-mediated pathways.
  • Tiam1-dependent ROS production is essential for sustaining ERK-mediated survival signaling.
  • Tiam1 regulates keratinocyte susceptibility to apoptosis by modulating the redox state and downstream signaling.

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