Abstracts
Résumé
L’état sénescent est un arrêt irréversible du cycle cellulaire associé à des modifications morphologiques et fonctionnelles de la cellule. La sénescence est causée par le raccourcissement des télomères (sénescence réplicative) ou par l’exposition aiguë ou chronique à d’autres signaux de stress physiologique (un phénomène appelé stasis, stress or aberrant signaling-induced senescence). Cet article traite des voies qui conduisent à la sénescence cellulaire, des mécanismes impliqués et du rôle de ces voies dans la régulation du déclenchement et de la progression tumorale. La sénescence réplicative ou la perte de fonctionnalité des télomères mobilisent les protéines détectrices des cassures double brin de l’ADN, conduisant à l’activation des systèmes de réparation de l’ADN et de la protéine suppresseur de tumeur p53, qui, à son tour, induit l’inhibiteur du cycle p21WAF1. L’inactivation de p53 et de pRb permet aux cellules de continuer à proliférer, mais les fonctions télomériques se détériorent jusqu’à la catastrophe génétique, ou crise. L’immortalisation étant un prérequis essentiel pour le développement des cellules tumorales, celles-ci doivent donc contourner au moins deux barrières prolifératives, la sénescence cellulaire et la crise, pour atteindre la transformation néoplasique. Ces barrières sont régulées par le raccourcissement des télomères et par les voies suppresseurs de tumeur p16INK4a/Rb et p53. L’identification des gènes et la connaissance des mécanismes régulateurs conduisant à la sénescence et déterminant le profil d’expression génique dans les cellules sénescentes pourraient conduire à des traitements anticancéreux plus efficaces.
Summary
Cells entering a state of senescence undergo a irreversible cell cycle arrest, associated by a set of functionnal and morphological changes. Senescence occurs following telomeres shortening (replicative senescence) or exposure to other acute or chronic physiologic stress signals (a phenomenon termed stasis : stress or aberrant signaling-induced senescence). In this review, I discuss the pathways of cellular senescence, the mechanisms involved and the role that these pathways have in regulating the initiation and progression of cancer. Telomere-initiated senescence or loss of telomere function trigger focal recruitement of protein sensors of the DNA double-strand breaks leading to the activation of the DNA damage checkpoint responses and the tumour suppressor gene product, p53, which in turn induces the cell-cycle inhibitor, p21WAF1. Loss of p53 and pRb function allows continued cell division despite increasing telomere dysfunction and eventually entry into telomere crisis. Immortalisation is an essential prerequisite for the formation of a tumour cell. Therefore, a developping tumour cell must circumvent at least two proliferative barriers - cellular senescence and crisis - to achieve neoplastic transformation. These barriers are regulated by telomere shortening and by the p16INK4a/Rb and p53 tumour suppressor pathways. Elucidation of the genes and emerging knowledge about the regulatory mechanisms that lead to senescence and determine the pattern of gene expression in senescent cells may lead to more effective treatments for cancer.
Appendices
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