CONCLUSIONS, DISCUSSIONS,
V. L’invalidation d’Api5 chez la souris est létale in utero.
La réalisation du KO d’Api5 chez la souris nous a permis de montrer que la perte homozygote d’Api5 entraîne une létalité embryonnaire qui survient à des stades précoces de la gestation (avant E6). Le stade exact de la létalité et le phénotype des embryons homozygotes API5 / n’ont pas été déterminées. Malheureusement, j’ai été confrontée à des limites techniques pour le travail avec des embryons aux premiers stades de développement.
Cependant le résultat obtenu nous permet d’ores et déjà de souligner l’importance de la fonction d’Api5 dans la prolifération cellulaire et ainsi qu’une absence de redondance
fonctionnelle, qui pourrait compenser sa perte. En effet, la létalité embryonnaire des souris KO est un événement observé mais rare, en raison de la redondance de fonction retrouvée au sein des familles de protéines mammifères. En mode d’illustration, les KO chez la souris d’E2F1 (et du reste des E2Fs sauf pour E2F3, Table 5), du FGF2 et de la plupart des Cyclines et Cdks (longtemps considérées comme des régulateurs clés et essentiels du cycle cellulaire) sont viables (Chen et al, 2009; Malumbres & Barbacid, 2009; Satyanarayana & Kaldis, 2009). La létalité du KO d’une protéine à un stade embryonnaire précoce souligne le caractère essentiel de son rôle dans la prolifération, dans le maintien de l’intégrité génétique ou dans l’embryogenèse au cours des premiers stades de développement. L’extraordinaire conservation de la séquence protéique d’Api5 au cours de l’évolution (Figure 40) est un argument additionnel à faveur du caractère essentiel de la protéine.
Figure 40. La séquence de la protéine Api5 est extrêmement conservée au cours de l’évolution. Alignement in silico à l’aide du logiciel «PRALINE» des séquences protéiques d’Api5 de six différentes espèces (Simossis & Heringa, 2005). Du haut au bas : Homo sapiens (Api5 524aa), Mus musculus (Api5 524aa), Galllus gallus (Api5 524aa), Xenopus laevis (Api5 524aa), Bos taurus (Api5 504aa) et Drosophila melanogaster (Api5 536aa). L’échelle de couleurs indiquant la conservation des acides aminés apparaît en haut de l’alignement.
De plus, les données bibliographiques et nos résultats montrent qu’Api5 joue une fonction modulatrice de l’activité pro mitotique et pro apoptotique du facteur de transcription E2F1 (Morris et al, 2006). Il est intéressant de constater que le KO de pRb chez la souris (le régulateur de l’activité E2F par excellence) est létal au stade embryonnaire, tout comme celui d’Api5 (Clarke et al, 1992; Jacks et al, 1992; Lee et al, 1992). Cependant, les embryons invalidés pour pRb meurent à mi gestation en raison d’une apoptose massive. Nous pouvons donc penser que les défauts présents dans les embryons invalidés pour Api5 ne sont pas provoqués par l’absence de son activité anti apoptotique, car dans ce cas nous aurions eu un phénotype similaire à celui de la souris KO pour pRb. La létalité de l’invalidation d’Api5 serait donc à mettre en relation avec son rôle d’activateur au niveau du cycle cellulaire. Dans ce sens, le KO de la kinase Cdk1, enzyme clé du cycle cellulaire, ainsi que les KO de ses deux régulateurs : les Cyclines A2 et B1, sont létaux chez la souris à des stades embryonnaires précoces (Brandeis et al, 1998; Murphy et al, 1997; Santamaria et al, 2007).
En conclusion, cette étude a traité de la fonction d’Api5, protéine modulatrice de l’activité du facteur de transcription d’E2F1. La protéine Api5, tout comme sa cible E2F1, est une protéine aux fonctions ambigües impliquées à la fois dans le déclenchement du cycle cellulaire et de l’apoptose en fonction du contexte cellulaire. La découverte du mécanisme moléculaire par lequel Api5 exerce sa régulation sur l’activité d’E2F1 me semble l’étape suivante impérative à la compréhension de la fonction d’Api5. De part son activité anti apoptotique décrite dans la bibliographie et son activité pro mitotique décrite dans ce travail, Api5 peut être considéré comme un proto oncogène impliqué dans la progression tumorale quand son expression ou son activité sont dérégulées. En illustration, Api5 est retrouvé surexprimé, ainsi qu’associé à une résistance au traitement et à des mauvais pronostics dans de nombreuses pathologies cancéreuses. Cependant, avec la réalisation du KO d’Api5 chez la souris, il apparaît qu’Api5 n’est pas seulement impliqué dans la progression tumorale dans un contexte pathologique, mais désormais Api5 doit être considéré et étudié en tant que régulateur essentiel à la prolifération et au développement embryonnaires.
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