TP53 regulation in developmental and oncogenic pathways

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Descripció

From differentiation and early stages of embryogenesis to cellular apoptosis and tumour suppression, the p53 transcription factor uptakes vital roles that preserve homeostasis. The TP53 gene, which is found mutated in >50% of any type of cancer, has evolved to guard the germline genome and protect the somatic cell. The DNA damage sensing pathway (MRN-ATM) and the DNA damage response pathway (DDR: ATM-MDM2-p53) activate p53 that in turn trans-activates downstream cell cycle arrest, DNA repair and apoptotic programs. Our understanding of the underlying mechanism whereby p53 is activated following genotoxic stress is constantly enriched. Under normal conditions, the activation of p53 is negatively regulated by the MDM2 E3 ubiquitin ligase, which binds the p53(BOX-I) motif (FxxxWxxL), signalling its degradation via the 26S proteasomal pathway. However, in response to double-stranded DNA breaks, the ATM kinase is activated and phosphorylates p53(Ser15), thus preventing the protein-protein interaction with MDM2. It also phosphorylates the MDM2(Ser395) facilitating the MDM2 - p53 mRNA interaction, which is required for MDM2-mediated activation of p53 via a previously presented mechanism whereby the secondary structure of the p53 mRNA plays a vital role. A single cancer-derived synonymous mutation (SM) in codon 22 (p53(L22L)) alters the secondary mRNA structure and averts the MDM2-p53 mRNA interaction. This mutation prevents the formation of the p53 mRNA-MDM2-RPL complex that recruits ATM to the p53 polysome to activate p53. This mechanism revealed potential clinical values of SMs in mutational profiling for precision medicine. With the aim to resolve the (i) structural/molecular and (ii) signalling interplay of p53, MDM2 and ATM, invertebrate models (Ciona intestinalis) expressing an ancestral form of p53; and the unique Elephant model, having evolved 20 p53 copies, are employed. In parallel with human cell lines and tissues, these systems allow the tracking of the interaction interfaces and the molecular evolution of p53 signalling. The presented project will describe the following aspects: - Mechanisms activating p53 and the implications of key SMs in the regulation of stress response. - Inter-species studies addressing how evolution lead to functional pools of molecules that retain p53 activities and their significance in development and cancer. - The physiological significance of the p53 interactions and their clinical relevance to therapies.

• Link: https://conectaha.csic.es/b/san-ewn-57a-efx.