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Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
09:18

Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death

Published on: December 27, 2016

Akt phosphorylation and stabilization of X-linked inhibitor of apoptosis protein (XIAP)

Han C Dan1, Mei Sun, Satoshi Kaneko

  • 1Departments of Pathology and Interdisciplinary Oncology, University of South Florida College of Medicine and H. Lee Moffitt Cancer Center, Tampa, Florida 33612, USA.

The Journal of Biological Chemistry
|December 3, 2003
PubMed

Insights

Akt phosphorylates XIAP, preventing its degradation and promoting cell survival. This discovery identifies XIAP as a key mediator of Akt

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Akt signaling pathway is crucial for cell survival, regulating apoptosis at pre- and post-mitochondrial levels.
  • Downstream targets of Akt in regulating post-mitochondrial cell death pathways are not fully elucidated.

Purpose of the Study:

  • To investigate the interaction between Akt and X-linked inhibitor of apoptosis protein (XIAP).
  • To determine if Akt phosphorylates XIAP and elucidate the functional consequences of this modification on cell survival and apoptosis.

Main Methods:

  • In vitro and in vivo experiments to assess Akt-XIAP interaction and XIAP phosphorylation at serine-87.
  • Analysis of XIAP ubiquitination, degradation, and autoubiquitination in response to cisplatin treatment.
  • Utilized XIAP mutants (S87D and S87A) to mimic or block Akt phosphorylation.
  • Investigated the role of XIAP in Akt-mediated cell survival using siRNA and antisense approaches in ovarian cancer cells.

Main Results:

  • Akt directly interacts with and phosphorylates XIAP at serine-87.
  • Akt-mediated phosphorylation of XIAP inhibits its ubiquitination and degradation, enhancing its stability.
  • XIAP phosphorylation by Akt also inhibits XIAP autoubiquitination.
  • XIAP-S87D mutant showed increased stability and enhanced cell survival post-cisplatin treatment.
  • XIAP-S87A mutant exhibited rapid degradation and increased cisplatin-induced apoptosis.
  • XIAP suppression induced apoptosis and blocked Akt-stimulated survival in ovarian cancer cells.

Conclusions:

  • XIAP is identified as a novel downstream target of Akt.
  • Akt-mediated phosphorylation of XIAP is a critical mechanism for promoting cell survival by stabilizing XIAP.
  • XIAP plays a significant role in mediating the anti-apoptotic effects of Akt, particularly in response to chemotherapy agents like cisplatin.

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