The tumor protein p63 (p63) encoded by the TP63 gene is a transcription factor of the p53 family. TP63 is essential for embryonic development, its absence prevents the establishment of the skin and is accompanied by malformations or total absence of upper limbs and defects in craniofacial morphogenesis. At the cellular level, TP63 is involved in stem cell renewal, cell differentiation and proliferation, promotion of epithelial-mesenchymal transition and maintenance of germline integrity. Alternative promoters and several alternative splicing events lead to the production of at least eight isoforms of p63. On the C-terminal side, there are four main isoforms: α, β, γ, and δ. The existence of multiple isoforms is often used to explain the complexity of TP63-dependent cellular events. TP63 is frequently amplified and/or overexpressed in squamous cell carcinomas, and we demonstrated a negative correlation between the expression level of the minority γ isoforms and survival of patients with head and neck squamous cell carcinomas. Through a combination of bioinformatics approaches and mechanistic analyses, I was able to demonstrate that a direct interaction between the RNA-binding protein PTBP1 and TP63 pre-messenger RNA represses the use of the terminal γ exon in a context of squamous cell carcinoma cell lines. The functional importance of this regulation is supported by its conservation from amphibians to humans. However, the functional consequences of altering the abundance of minority isoforms of p63 remains an open question.
Composition of the jury :
- Pr. Marie-Dominique Galibert;
- Dr Pierre Busson;
- Dr Reini Fernandez de Luco;
- Dr Yann Audic