The dominant-negative interplay between p53, p63 and p73: A family affair

// Olivier Billant 1 , Alice Leon 1 , Solenn Le Guellec 1 , Gaelle Friocourt 1 , Marc Blondel 1, * , Cecile Voisset 1, * 1 Inserm UMR 1078, Universite de Bretagne Occidentale, Faculte de Medecine et des Sciences de la Sante, Etablissement Francais du Sang (EFS) Bretagne, CHRU Brest, Hopital Morvan, Laboratoire de Genetique Moleculaire, Brest, France * These authors contributed equally to this work Correspondence to: Cecile Voisset, email: cecile.voisset@univ-brest.fr Marc Blondel, email: marc.blondel@univ-brest.fr Keywords: p53, p63, p73, dominant-negative effect, yeast Received: May 01, 2016      Accepted: July 10, 2016      Published: August 31, 2016 ABSTRACT The tumor suppression activity of p53 is frequently impaired in cancers even when a wild-type copy of the gene is still present, suggesting that a dominant-negative effect is exerted by some of p53 mutants and isoforms. p63 and p73, which are related to p53, have also been reported to be subjected to a similar loss of function, suggesting that a dominant-negative interplay might happen between p53, p63 and p73. However, to which extent p53 hotspot mutants and isoforms of p53, p63 and p73 are able to interfere with the tumor suppressive activity of their siblings as well as the underlying mechanisms remain undeciphered. Using yeast, we showed that a dominant-negative effect is widely spread within the p53/p63/p73 family as all p53 loss-of-function hotspot mutants and several of the isoforms of p53 and p73 tested exhibit a dominant-negative potential. In addition, we found that this dominant-negative effect over p53 wild-type is based on tetramer poisoning through the formation of inactive hetero-tetramers and does not rely on a prion-like mechanism contrary to what has been previously suggested. We also showed that mutant p53-R175H gains the ability to inhibit p63 and p73 activity by a mechanism that is only partially based on tetramerization.