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CIAP1 and the serine protease HTRA2 are involved in a novel p53-dependent apoptosis pathway in mammals

Shengkan Jin1, Markus Kalkum, Michael Overholtzer

  • 1Laboratory of Cancer Biology, Rockefeller University, New York, New York 10021, USA.

Genes & Development
|February 6, 2003
PubMed

Insights

Mammalian p53 protein triggers apoptosis by activating HTRA2, a serine protease that cleaves and inhibits CIAP1, a key inhibitor of apoptosis. This pathway mirrors a novel mechanism found in Drosophila, highlighting conserved apoptosis regulation.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Apoptosis Research

Background:

  • Drosophila p53 protein mediates apoptosis via Reaper gene activation and inhibition of apoptosis (IAPs).
  • Mammalian Inhibitors of Apoptosis Proteins (IAPs) play crucial roles in regulating cell death.
  • Understanding conserved apoptosis pathways is vital for cancer research and therapeutics.

Purpose of the Study:

  • To investigate the role of mammalian p53 in apoptosis.
  • To identify the molecular mechanisms linking p53 activation to apoptosis in mammals.
  • To explore the functional similarity between Drosophila and mammalian p53-mediated apoptosis pathways.

Main Methods:

  • Investigated the cleavage of CIAP1 (a mammalian IAP homolog) during p53-dependent apoptosis.
  • Utilized serine protease inhibitors to block CIAP1 cleavage and assess apoptosis.
  • Analyzed the transcriptional regulation of the HTRA2 gene in response to p53 activation.

Main Results:

  • CIAP1 is irreversibly cleaved by a serine protease during p53-dependent apoptosis.
  • Inhibition of CIAP1 cleavage by serine protease inhibitors blocked p53-dependent apoptosis.
  • p53 activation led to increased transcription of the HTRA2 gene, encoding a serine protease that interacts with CIAP1.

Conclusions:

  • Mammalian p53 protein activates apoptosis through a novel pathway involving HTRA2.
  • HTRA2, a serine protease, potentiates apoptosis by cleaving and inhibiting CIAP1.
  • This mammalian pathway is functionally similar to the novel Drosophila p53-mediated apoptosis pathway.

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