Mechanism of TAp73 inhibition by ΔNp63 and structural basis of p63/p73 hetero-tetramerization

Abstract

Members of the p53 tumor-suppressor family are expressed as multiple isoforms. Isoforms with an N-terminal transactivation domain are transcriptionally active, while those ones lacking this domain often inhibit the transcriptional activity of other family members. In squamous cell carcinomas, the high expression level of ΔNp63α inhibits the tumor-suppressor function of TAp73β. This can in principle be due to blocking of the promoter or by direct interaction between both proteins. p63 and p73 can heterooligomerize through their tetramerization domains and a hetero-tetramer consisting of two p63 and two p73 molecules is thermodynamically more stable than both homo-tetramers. Here we show that cells expressing both p63 and p73 exist in mouse epidermis and hair follicle and that hetero-tetramer complexes can be detected by immunoprecipitation in differentiating keratinocytes. Through structure determination of the hetero-tetramer, we reveal why this hetero-tetramer is the thermodynamically preferred species. We have created mutants that exclusively form either hetero-tetramers or homo-tetramers, allowing to investigate the function of these p63/p73 hetero-tetramers. Using these tools, we show that inhibition of TAp73β in squamous cell carcinomas is due to promoter squelching and not direct interaction.

Reactivation of TAp73 tumor suppressor by protoporphyrin IX, a metabolite of aminolevulinic acid, induces apoptosis in TP53-deficient cancer cells

“…Consistently, PpIX was shown to induce cancer cell death in sarcoma cells 25 . In line with our data (Figure 1d Recently, detailed analysis of the oligomeric state of TAp73 alpha by Melino and Dötsch labs revealed a high structure homology between p53 and p73 tetramers 26 .…”

ROCK ‐dependent phosphorylation of NUP 62 regulates p63 nuclear transport and squamous cell carcinoma proliferation

“…Furthermore, previous studies demonstrated the mechanistic action of ΔNp63α in SCC . For example, ΔNp63α inhibits the activity of TAp73 via transcriptional inhibition and, to a lesser extent, direct interaction between both proteins . Therefore, attenuation of ΔNp63α nuclear transport can serve as a new strategy to compromise its functions.…”

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].…”