Abstracts
Résumé
La régulation transcriptionnelle de l’expression de p16INK4a constitue un pivot essentiel lors du vieillissement cellulaire et de la réponse à un stress, en particulier oncogénique. Cette régulation, complexe, implique des facteurs activateurs (protéines Ets1 et -2, protéine E47), dont la liaison sur le promoteur du gène INK4a peut être inhibée par les protéines Id-1 ou -4. L’inhibition transcriptionnelle de p16INK4a repose également sur le répresseur transcriptionnel Bmi1, ainsi que sur une régulation épigénétique complexe, dont le mécanisme est seulement partiellement connu : le promoteur et l’exon 1 de INK4a présentent tous deux un îlot CpG, qui peut être méthylé après qu’une méthylation de l’histone H3 et une désacétylation de l’histone H4 soient intervenues, tous ces événements participant à l’extinction du gène. À l’inverse, le gène INK4a serait protégé de la méthylation de ses ilôts CpG par l’hélicase A de l’ARN, et le remodelage chromatinien faisant intervenir le complexe SWI/SNF, antagoniste de Bmi1, activerait l’expression de INK4a. L’analyse de la complexité des différents mécanismes de régulation de INK4a et une meilleure compréhension des modulations épigénétiques de son expression devraient permettre de développer l’utilisation rationnelle de nouvelles stratégies thérapeutiques anticancéreuses.
Summary
The transcriptional regulation of p16INK4a is essential for cellular aging and oncogenic stress response. This regulation involves p16INK4a transcriptional activators such as proteins Ets1 and 2 or E47. The binding of these proteins to INK4a promoter can be inhibited by proteins Id-1 or -4 after heterodimer formation. The transcriptional inhibition of p16INK4a includes also the transcriptional repression by Bmi-1, and an epigenetic regulation which appears complex and remains incompletely understood. Actually, INK4a promoter and exon1 present a CpG island which can be methylated on cytosines by DNA methyltransferases. This DNA methylation is preceded by the lysine 9 histone H3 methylation and by the deacetylation of histone H4 both involved in gene silencing. Indeed, RNA Helicase A might protect INK4a against methylation of CpG island. Furthermore, chromatin remodelling involving SWI/SNF complex, antagonist to Bmi-1, might activate INK4a expression. The analysis of INK4a regulation mechanisms and the comprehension of the epigenetic modulation of its expression may allow us to develop a rational use of new anti-neoplastic agents.
Appendices
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