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Updated: May 19, 2026

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

AATF/Che-1 acts as a phosphorylation-dependent molecular modulator to repress p53-driven apoptosis

Katja Höpker1, Henning Hagmann, Safiya Khurshid

  • 1Department II of Internal Medicine, University Hospital of Cologne, Cologne, Germany.

The EMBO Journal
|August 23, 2012
PubMed

Insights

The apoptosis-antagonizing transcription factor (AATF) regulates cell fate after DNA damage. Phosphorylated AATF prevents p53-driven apoptosis, enhancing chemotherapy resistance in tumors.

Area of Science:

  • Cellular biology
  • Molecular oncology
  • Signal transduction

Background:

  • Genotoxic stress triggers cell cycle arrest and DNA repair or apoptosis.
  • The tumor suppressor p53 is central to the DNA damage response.
  • Signaling molecules determining cell fate after DNA damage are not fully understood.

Purpose of the Study:

  • Identify critical regulators of the p53 response outcome.
  • Investigate the role of apoptosis-antagonizing transcription factor (AATF)/Che-1 in DNA damage response.
  • Determine the therapeutic potential of targeting the p38/MK2/AATF pathway.

Main Methods:

  • Investigated AATF phosphorylation by MK2 upon genotoxic stress.
  • Examined AATF nuclear translocation and binding to pro-apoptotic gene promoters (PUMA, BAX, BAK).
  • Utilized xenograft models, AATF depletion, and phospho-mimicking AATF mutants to assess chemotherapy response.
  • Analyzed AATF locus copy number and expression in human cancers (endometrial, neuroblastoma).

Main Results:

  • AATF phosphorylation by MK2 releases it from the cytoplasm, leading to nuclear translocation.
  • Nuclear AATF represses p53-driven expression of pro-apoptotic genes PUMA, BAX, and BAK.
  • AATF depletion enhances tumor response to adriamycin chemotherapy in vivo.
  • A phospho-mimicking AATF mutant confers adriamycin resistance.
  • Nuclear AATF enrichment is observed in p53-proficient endometrial cancers.
  • Focal copy number gains at the AATF locus in neuroblastoma correlate with poor prognosis.

Conclusions:

  • The p38/MK2/AATF signaling module critically represses p53-driven apoptosis.
  • AATF acts as a key determinant of cellular fate following genotoxic stress.
  • The AATF pathway represents a potential therapeutic target for sensitizing tumors to DNA damage-inducing agents.

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