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Caspase-9 can antagonize p53-induced apoptosis by generating a p76(Rb) truncated form of Rb

Christophe Lemaire1, Nelly Godefroy, Ioana Costina-Parvu

  • 1Laboratoire de Génétique et Biologie Cellulaire, CNRS FRE 2445, Université de Versailles/St Quentin-en-Yvelines, 45 avenue des Etats-Unis, 78035 Versailles cedex, France.

Oncogene
|March 1, 2005
PubMed

Insights

Caspase-9 antagonizes p53-induced apoptosis by cleaving the retinoblastoma protein (Rb) into a protective p76(Rb) form. This pre-mitochondrial pathway reveals a novel anti-apoptotic function for truncated Rb.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • The tumor suppressor retinoblastoma protein (Rb) regulates p53-dependent apoptosis.
  • Mechanisms by which Rb influences p53-mediated apoptosis are not fully understood.
  • Previous studies suggested caspases antagonize p53-induced apoptosis by generating a protective truncated Rb form.

Purpose of the Study:

  • To identify the specific caspase involved in antagonizing p53-induced apoptosis.
  • To elucidate the mechanism of Rb cleavage and its role in apoptosis regulation.
  • To characterize the anti-apoptotic function of truncated Rb forms.

Main Methods:

  • Utilized a rat fibroblast model (both immortalized and primary).
  • Employed caspase inhibition assays to study apoptosis.
  • Analyzed Rb cleavage products and identified specific caspase activity.
  • Investigated caspase processing and localization in living cells.

Main Results:

  • Identified caspase-9 as the key caspase interfering with p53-induced apoptosis upstream of the mitochondrion.
  • Demonstrated that caspase-9 is processed by p38 in living cells prior to apoptosome formation.
  • Revealed a novel cleavage of Rb at a LExD site, generating a p76(Rb) form.
  • Showed that this p76(Rb) form antagonizes p53-induced apoptosis.

Conclusions:

  • Caspase-9 plays a critical role in a pre-mitochondrial pathway that protects against p53-induced apoptosis.
  • Cleavage of Rb by caspase-9 generates an anti-apoptotic p76(Rb) fragment.
  • Truncated Rb forms can exert anti-apoptotic activity, challenging the view of them solely as degradation byproducts.

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