When did the gene coding for p53 appear during evolution?
What is thefunction of TP53 variants heterogenity in human cancer ?
These two questions constituted the basis of my work performed during my Post Doctoral research in the laboratory of P. May, one of the discoverer of TP53 and have drive my research for more than 30 years.
Despite their apparent divergence, the answers to these two questions are interrelated.
Phylogenetic analysis has become an essential technique to investigate the processes and the patterns of species evolution and for the prediction of functionally important residues. Understanding how proteins can adapt their function to novel cellular environment conditions such as temperature, pH or ionic strength, is essential for decrypting their structure-function relationships. In this constructive process, the evolutionary pressure selects the best-fitted product, leading to an optimal homeostasis of the cell. Disease-associated genetic alterations have the exact opposite effect, with mutations leading to irreversible changes in the function of the product, ranging from a total or partial loss of function to the acquisition of novel pathogenic functions. Disease-associated amino-acid changes occur more often at evolutionarily conserved residues, and sequence conservation has been widely used to predict the severity of genetic variants.
The tumor suppressor p53, a tetrameric transcription factor, is an ideal paradigm for studying the effect of disease mutations and principles of protein evolution. The TP53 gene is inactivated by mutation in about half of all human cancers and is therefore a prime target in cancer therapy.
Guest professor, Karolinska Intitutet, 2005- present
Professor of Molecular Biology (Class I), University P. & M. Curie, 2000- present
Professor of Molecular Biology (Class II), University P. & M. Curie, 1992-1999
Assistant Professor (class II), University P. & M. Curie, 1989-1991
Assistant Professor (class I), University P. & M. Curie, 1983-1988
- First thesis: SV40 DNA Replication, Laboratoire d'Enzymologie, IRSC Villejuif, Dr A.M. de Recondo, 1979-1983
- Second thesis: Phylogenetic analysis of the p53 gene, Laboratoire d'Oncologie Moléculaire, IRSC Villejuif, Dr P. May, 1984-1988
Six selected publications (among 253):