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GRAMD4 mimics p53 and mediates the apoptotic function of p73 at mitochondria

K John1, V Alla, C Meier

  • 1Department of Vectorology and Experimental Gene Therapy, Biomedical Research Center, University of Rostock, Schillingallee 69, Rostock, Germany.

Cell Death and Differentiation
|December 4, 2010
PubMed

Insights

The tumor suppressor p73 triggers apoptosis through the mitochondria by activating GRAMD4, a novel pro-apoptotic protein. This p73-GRAMD4 pathway enhances cancer cell killing, supporting p73

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • p73, a p53 family member, exhibits p53-like functions including apoptosis induction.
  • The mitochondrial pathway of apoptosis controlled by p73 remains incompletely understood.
  • GRAMD4 is a previously identified mitochondrial pro-apoptotic protein regulated by E2F1.

Purpose of the Study:

  • To investigate the role of GRAMD4 in p73-mediated apoptosis.
  • To elucidate the downstream mitochondrial mechanism of p73-induced cell death.

Main Methods:

  • Analysis of p73 isoforms (p73α, p73β) and p53 in apoptosis induction.
  • Investigation of GRAMD4 expression, mitochondrial localization, and interaction with Bcl-2 and Bax.
  • Assessment of mitochondrial membrane permeabilization and cytochrome c release.
  • Evaluation of GRAMD4 transcription activation by p73 and response to cisplatin (cDDP).
  • In vivo studies using solid tumor xenografts.

Main Results:

  • p73 induces apoptosis via GRAMD4 expression and mitochondrial translocation.
  • GRAMD4 interacts with Bcl-2, promotes Bax relocalization, and triggers mitochondrial outer membrane permeabilization.
  • p73α and p73β, but not p53, directly transactivate the GRAMD4 promoter.
  • GRAMD4 expression is upregulated by cisplatin in a p73-dependent manner.
  • Co-expression of GRAMD4 and cisplatin enhances cancer cell killing in vivo.

Conclusions:

  • p73 triggers apoptosis through the mitochondrial pathway via GRAMD4 as a novel mediator.
  • The p73-GRAMD4 axis represents a new mechanism for p53-like tumor suppressor functions.
  • Targeting the p73-GRAMD4 pathway holds potential for cancer therapy.

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