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The G2/M regulator 14-3-3sigma prevents apoptosis through sequestration of Bax

T Samuel1, H O Weber, P Rauch

  • 1Laboratory of Molecular Tumor Biology, Department of Dermatology, University of Erlangen-Nuremberg, 91052 Erlangen, Germany.

The Journal of Biological Chemistry
|September 28, 2001
PubMed

Insights

Colorectal tumor cells lacking 14-3-3sigma (sigma) undergo rapid apoptosis upon DNA damage. Reintroducing sigma protein rescues these cells, revealing its crucial anti-apoptotic role.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Biology

Background:

  • The p53 tumor suppressor induces cell cycle arrest or apoptosis in response to DNA damage.
  • 14-3-3sigma (sigma) is a p53 target gene that mediates G2 arrest following DNA damage.
  • Colorectal tumor cells deficient in sigma exhibit extreme sensitivity to genotoxic stress.

Purpose of the Study:

  • To elucidate the mechanism underlying the heightened sensitivity of sigma-deficient colorectal tumor cells to DNA damage.
  • To compare the cellular response to adriamycin in sigma-null (sigma-/-) versus sigma-positive (sigma+/+) human colorectal tumor cells.

Main Methods:

  • Adriamycin exposure was used to induce DNA damage in sigma-/- and sigma+/+ colorectal tumor cells.
  • Apoptosis markers including caspase-3 activation, p21CIP1 cleavage, CDK2 activation, Bax translocation, and cytochrome c release were analyzed.
  • Adenovirus-mediated gene transfer was employed to reintroduce sigma into sigma-/- cells.

Main Results:

  • Sigma-/- cells underwent rapid apoptosis upon adriamycin treatment, unlike sigma+/+ cells.
  • Key apoptotic events, including caspase-3 activation and Bax translocation, were accelerated in sigma-/- cells.
  • Reconstitution of sigma expression in sigma-/- cells effectively rescued the apoptotic phenotype and conferred resistance to DNA damage-induced cell death.

Conclusions:

  • 14-3-3sigma plays a critical role in preventing apoptosis in colorectal tumor cells exposed to DNA damage.
  • The anti-apoptotic function of sigma may involve its association with proteins like Bax and CDK1 in protein complexes.
  • Sigma not only enforces p53-dependent G2 arrest but also actively delays apoptotic signaling pathways.

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