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

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.

Integrin-β4 is a novel transcriptional target of TAp73

“…p53 family can be considered among the most powerful family of genes for the wide range of functions covering from tumour suppression, homeostasis and development [1][2][3][4][5][6][7][8][9][10][11]. In this context the p53 family member p73 plays critical roles such as tumour suppression [12][13][14][15][16][17], neuronal development and differentiation [18][19][20][21][22][23][24], metabolic control [25][26][27][28][29][30][31][32][33], and spermatogenesis and the maintenance of male and female fertility [34][35][36][37].…”

Role of p53 family isoforms in enhancing aggressiveness and chemoresistance in pancreatic cancer (Review)

“…Strong genotoxic stress activates p53 and promotes cell cycle arrest, cellular senescence and apoptosis, while mild genotoxic stress can activate pathways responsible for repair mechanisms (17,20,32,33). On its own, p53 has 12 different isoforms with similar or unique functions, as a result of alternate splicing, the presence of diverse transcription promoters, as well as multiple translation initiation sites (32,34,35). In human cancer, p53 inactivation by mutation occurs in >50% of cases, and therefore, it is known to be the most common genetic alteration (36,37).…”

Structural-functional diversity of p53 proteoforms

“…Многие мутации могут вызывать доминантно-негативный эффект (DNE), то есть ингибирующий эффект по отношению к белку р53 дикого типа, приводя к злокачественной трансформации клеток. Одним из возможных путей проявления доминантно-негативного эффекта считается гетероолигомеризация, то есть образование гетеротетрамеров р53, которые потенциально могут связываться с ДНК слабее, чем гомотетрамеры р53 [44]. В противоположность другим онкосупрессорам, для которых характерны мутации, прекращающие синтез белка, в случае р53 -это чаще всего миссенс мутации, которые возникают в ДНК-связывающем домене (более 80%).…”