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Acute ablation of survivin uncovers p53-dependent mitotic checkpoint functions and control of mitochondrial apoptosis

Elena Beltrami1, Janet Plescia, John C Wilkinson

  • 1Department of Cancer Biology and the Cancer Center, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA.

The Journal of Biological Chemistry
|October 29, 2003
PubMed

Insights

Survivin protein ablation causes cell cycle arrest and polyploidy by disrupting mitosis. Loss of survivin also impacts apoptosis, with cytosolic survivin crucial for mitochondrial integrity and cell survival.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • Survivin, an Inhibitor of Apoptosis family member, plays roles in cell division and apoptosis suppression.
  • The precise functions of survivin's subcellular pools in cell cycle control and apoptosis remain incompletely understood.

Purpose of the Study:

  • To investigate the distinct roles of nuclear and cytosolic survivin in mitosis and apoptosis.
  • To elucidate the molecular mechanisms underlying survivin's checkpoint functions.

Main Methods:

  • RNA interference (RNAi) for targeted survivin ablation in nuclear and cytosolic pools.
  • Analysis of cell cycle progression, polyploidy, centrosome integrity, spindle formation, and chromatin segregation.
  • Investigation of p53 and p21(Waf1/Cip1) roles in survivin-depleted cells.
  • Assessment of apoptosis induction, mitochondrial membrane potential, and caspase-9 activation.

Main Results:

  • Preferential nuclear survivin ablation induced mitotic arrest, re-entry into the cell cycle, and polyploidy.
  • Survivin loss caused centrosomal defects, multipolar spindles, and chromatin missegregation, exacerbated by p21(Waf1/Cip1) deficiency.
  • Mitotic checkpoint activation involved p53 induction and p21(Waf1/Cip1) upregulation.
  • p53-deficient cells showed reduced mitotic arrest and increased polyploidy upon survivin ablation.
  • Partial cytosolic survivin reduction sensitized cells to UVB-induced apoptosis via enhanced caspase-9 cleavage.
  • Complete cytosolic survivin ablation led to mitochondrial membrane potential loss and spontaneous apoptosis.

Conclusions:

  • Survivin exhibits separable checkpoint functions in mitosis and mitochondrial-dependent apoptosis.
  • Nuclear survivin is critical for proper mitotic progression and chromosome segregation.
  • Cytosolic survivin plays a key role in maintaining mitochondrial integrity and preventing spontaneous apoptosis.

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