Biomedical subjects
Philippe Sanseau
Publications and source records attributed to Philippe Sanseau.
A computational view of microRNAs and their targets.
Small non-coding RNAs called microRNAs have been shown to play important roles in gene regulation across a broad range of metazoans from plants to humans. In this review, the nature and function of microRNAs will be discussed, with special emphasis on the computational tools and databases available to predict microRNAs and the genes they target.
Evolutionary relationships of Aurora kinases: implications for model organism studies and the development of anti-cancer drugs.
BACKGROUND: As key regulators of mitotic chromosome segregation, the Aurora family of serine/threonine kinases play an important role in cell division. Abnormalities in Aurora kinases have been strongly linked with cancer, which has lead to the recent development of new classes of anti-cancer drugs that specifically target the ATP-binding domain of these kinases. From an evolutionary perspective, the species distribution of the Aurora kinase family is complex. Mammals uniquely have three Aurora kinases, Aurora-A, Aurora-B, and Aurora-C, while for other metazoans, including the frog, fruitfly and nematode, only Aurora-A and Aurora-B kinases are known. The fungi have a single Aurora-like homolog. Based on the tacit assumption of orthology to human counterparts, model organism studies have been central to the functional characterization of Aurora kinases. However, the ortholog and paralog relationships of these kinases across various species have not been rigorously examined. Here, we present comprehensive evolutionary analyses of the Aurora kinase family. RESULTS: Phylogenetic trees suggest that all three vertebrate Auroras evolved from a single urochordate ancestor. Specifically, Aurora-A is an orthologous lineage in cold-blooded vertebrates and mammals, while structurally similar Aurora-B and Aurora-C evolved more recently in mammals from a duplication of an ancestral Aurora-B/C gene found in cold-blooded vertebrates. All so-called Aurora-A and Aurora-B kinases of non-chordates are ancestral to the clade of chordate Auroras and, therefore, are not strictly orthologous to vertebrate counterparts. Comparisons of human Aurora-B and Aurora-C sequences to the resolved 3D structure of human Aurora-A lends further support to the evolutionary scenario that vertebrate Aurora-B and Aurora-C are closely related paralogs. Of the 26 residues lining the ATP-binding active site, only three were variant and all were specific to Aurora-A. CONCLUSIONS: In this study, we found that invertebrate Aurora-A and Aurora-B kinases are highly divergent protein families from their chordate counterparts. Furthermore, while the Aurora-A family is ubiquitous among all vertebrates, the Aurora-B and Aurora-C families in humans arose from a gene duplication event in mammals. These findings show the importance of understanding evolutionary relationships in the interpretation and transference of knowledge from studies of model organism systems to human cellular biology. In addition, given the important role of Aurora kinases in cancer, evolutionary analysis and comparisons of ATP-binding domains suggest a rationale for designing dual action anti-tumor drugs that inhibit both Aurora-B and Aurora-C kinases.
In silico identification of novel therapeutic targets.
The availability of the human genome sequence is a 'once in a lifetime' opportunity for scientists to uncover all possible human drug-targets. As the sequence is very large, the best way to identify new genes rapidly is by computational (in silico) methods. There are now many examples in which pharmaceutical companies have identified genes of interest initially by in silico analysis. High-throughput data-generation techniques, such as microarray analysis, are key to the generation of human genome data. Bioinformatics techniques are therefore certain to play an increasingly important role in drug discovery.