Research

Resistance of mitochondrial p53 to dominant inhibition

Kristina Heyne¹ , Katrin Schmitt¹ , Daniel Mueller¹ , Vivienne Armbruester¹ , Pedro Mestres² and Klaus Roemer¹

¹  Internal Medicine I, José-Carreras-Research Center, Bldg. 45.3, University of Saarland Medical School, 66421 Homburg/Saar, Germany

²  Anatomy and Electron Microscopy, University of Saarland Medical School, 66421 Homburg/Saar, Germany

author email corresponding author email

Molecular Cancer 2008, 7:54doi:10.1186/1476-4598-7-54

Published:	12 June 2008

Abstract

Background

Mutation of a tumor suppressor allele leaves the second as backup. Not necessarily so with p53. This homo-tetrameric transcription factor can become contaminated with mutant p53 through hetero-tetramerization. In addition, it can be out-competed by the binding to p53 DNA recognition motifs of transactivation-incompetent isoforms (ΔN and ΔTA-isoforms) of the p53/p63/p73 family of proteins. Countermeasures against such dominant-negative or dominant-inhibitory action might include the evolutionary gain of novel, transactivation-independent tumor suppressor functions by the wild-type monomer.

Results

Here we have studied, mostly in human HCT116 colon adenocarcinoma cells with an intact p53 pathway, the effects of dominant-inhibitory p53 mutants and of Δex2/3p73, a tumor-associated ΔTA-competitor of wild-type p53, on the nuclear transactivation-dependent and extra-nuclear transactivation-independent functions of wild-type p53. We report that mutant p53 and Δex2/3p73, expressed from a single gene copy per cell, interfere with the stress-induced expression of p53-responsive genes but leave the extra-nuclear apoptosis by mitochondrial p53 largely unaffected, although both wild-type and mutant p53 associate with the mitochondria. In accord with these observations, we present evidence that in contrast to nuclear p53 the vast majority of mitochondrial p53, be it wild-type or mutant, is consisting of monomeric protein.

Conclusion

The extra-nuclear p53-dependent apoptosis may constitute a fail-safe mechanism against dominant inhibition.