Design of a compound that stabilizes the main natural suppressor...( This press release is available in...)

This press release is available in Spanish.

An interdisciplinary team of researchers, headed by Ernest Giralt at the Institute for Research in Biomedicine (IRB Barcelona) and Javier de Mendoza at the "Institut Catal d'Investigaci Qumica" (ICIQ, Tarragona), have discovered a substance with the capacity to maintain protein p53 stable even when it presents certain mutations that promote the appearance of cancer. Giralt, head of the Chemistry and Molecular Pharmacology programme and senior professor at the University of Barcelona, explains that, "tentatively, this could be the starting point to develop a new approach for anti-tumour treatments". The study has been published today in the journal Proceedings of the National Academy of Sciences (PNAS) in an advanced edition.

Protein p53 is considered the most important tumour suppressor and it is at the centre of the machinery that regulates cell cycle arrest and the death of cells with damaged DNA. In its active form, p53 protein is a tetramer, that is to say it is formed by four identical copies of proteins bound together, which has four domains with differentiated functions: activation of transcription, DNA binding, tetramerization and regulation. The tetramerization domain is responsible for stabilizing the tetrameric structure.

More than 50% of cancer patients have mutations in the p53 gene. Although most of these are located in the DNA binding domain, several mutations are found in the tetramerization domain, thereby causing destabilization of the entire protein with the consequent loss of activity. Two well documented examples of this kind of congenital predisposition are pediatric adrenocortical carcinoma and Li-Fraumeni syndrome. Therefore, the design of compounds with the capacity to stabilize the tetramerization domain of p53 represents a new and attractive strategy for the development of
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