Chapitre 4 : Perspectives
4.5 Déterminer l’implication de HIF-1 dans le SAO
Enfin, nos travaux ont montré que DOCK6 régule l’expression de HIF-1α via le contrôle de la voie MAPK et, en contrepartie, que HIF-1 module l’expression de DOCK6 en condition hypoxique. Puisque DOCK6 est impliquée dans le développement du syndrome Adams-Oliver, il serait intéressant de vérifier si HIF-1 détient également un rôle à jouer dans le SAO ou dans le développement de complications associées à cette pathologie. En effet, le SAO entraine plusieurs anomalies, dont des troubles cardiaques et vasculaires ainsi que de l’hypertension pulmonaire. Ces processus font intervenir une composante hypoxique ainsi que l’implication du facteur de transcription HIF-1, suggérant
dans cette maladie, nous pourrions développer un modèle animal du SAO en insérant une mutation tronquante dans le gène DOCK6 et effectuer des immunohistochimies sur les tissus présentant des défauts de développement. La maladie affecte en effet le développement de plusieurs tissus, dont le cerveau, les poumons et les reins (144). Il sera donc intéressant d’étudier l’expression de HIF-1 dans ces différents tissus.
Conclusion
Les résultats abordés dans le présent mémoire de maîtrise peuvent être résumés par la Figure 23. La représentation de nos résultats est déclinée selon deux situations, soit selon une condition d’oxygénation normale (21% O2) ou selon une condition hypoxique (1% O2).
Nos travaux récents ont permis de montrer que l’arginine méthyltransférase PRMT1 bloque l’expression de HIF-1α via la répression des facteurs de transcription Sp1/3 par l’inhibition de la voie MAPK. Nos travaux ont également permis d’identifier DOCK6 comme partenaire d’interaction de PRMT1 et comme intermédiaire dans la régulation de la voie MAPK et dans le contrôle d’expression de HIF-1α. Ces résultats sont représentés à la
Figure 23A. Pour résumer, en condition normale d’oxygénation, l’interaction entre
DOCK6 et PRMT1 provoque la méthylation de DOCK6 et l’inhibition de son activité GEF. L’inhibition de l’activité GEF de DOCK6 empêche la liaison de la GTPase RAC1 à un GTP, ce qui bloque la phosphorylation de la kinase PAK1 et l’activation de la voie MAPK en aval. En conséquence, l’inhibition de la voie MAPK bloque l’activité des facteurs de transcription Sp1/3 ce qui empêche la transcription et l’expression du facteur HIF-1α.
Ce mécanisme de régulation est renversé en hypoxie. En effet, les travaux présentés dans ce mémoire montrent que le facteur de transcription HIF-1 régule positivement l’expression de la protéine DOCK6. Nous avons également montré que la protéine DOCK6 non méthylée par PRMT1 agit plutôt comme un activateur de la voie MAPK. De plus, comme il a été mentionné précédemment, l’activité de PRMT1 est inhibée en hypoxie (136- 138). D’après ces informations, nous proposons donc le modèle présenté à la Figure 22B. Ce modèle montre que l’expression de DOCK6 régulée par le facteur de transcription HIF- 1 ainsi que l’inhibition de PRMT1 via l’hypoxie induisent l’activation de la voie MAPK en condition hypoxique.
Figure 23. Modèle représentant la dynamique entre la régulation d'expression de HIF-1α par PRMT1 via la voie MAPK et DOCK6
HIF1A HIF2A HIF-α Sp1/3 PRMT1 RAF MEK ERK ERK P P P P PAK1 Ras P GTP GDP P DOCK6 Rac1 CH3 HIF1A HIF2A HIF-α Sp1/3 PRMT1 RAF MEK ERK ERK P P P P PAK1 Ras P GTP GDP P DOCK6 Rac1 CH3 HIF-β DOCK6 PRMT1 GTP GDP B GTP GDP A
(A) Représentation schématique de la régulation d’expression de HIF-1α en normoxie via la méthylation de DOCK6 par PRMT1. (B) Représentation schématique de la régulation d’expression de DOCK6 et de l’activation de la voie MAPK en hypoxie via l’inhibition de PRMT1. Illustration adaptée avec permission de V.N. Lafleur (31)
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