HIF1 transcription factor regulates laminin-332 expression and keratinocyte migration.
Epidermal wound repair is a complex process involving the fine orchestrated regulation of crucial cell functions, such as proliferation, adhesion and migration. Using an in vitro model that recapitulates central aspects of epidermal wound healing, we demonstrate that the transcription factor HIF1 is strongly stimulated in keratinocyte cultures submitted to mechanical injury. Signals generated by scratch wounding stabilise the HIF1alpha protein, which requires activation of the PI3K pathway independently of oxygen availability. We further show that upregulation of HIF1alpha plays an essential role in keratinocyte migration during the in vitro healing process, because HIF1alpha inhibition dramatically delays the wound closure. In this context, we demonstrate that HIF1 controls the expression of laminin-332, one of the major epithelial cell adhesion ligands involved in cell migration and invasion. Indeed, silencing of HIF1alpha abrogates injury-induced laminin-332 expression, and we provide evidence that HIF1 directly regulates the promoter activity of the laminin alpha3 chain. Our results suggest that HIF1 contributes to keratinocyte migration and thus to the re-epithelialisation process by regulating laminin-332.
Fitsialos
Giorgos
G
INSERM U634, F-06107 Nice, France.
Bourget
Isabelle
I
Augier
Séverine
S
Ginouvès
Amandine
A
Rezzonico
Roger
R
Odorisio
Teresa
T
Cianfarani
Francesca
F
Virolle
Thierry
T
Pouysségur
Jacques
J
Meneguzzi
Guerrino
G
Berra
Edurne
E
Ponzio
Gilles
G
Buscà
Roser
R
D000818:Animals; D001483:Base Sequence; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000502:physiology*; D007797:Laminin / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011401:Promoter Regions, Genetic; D015398:Signal Transduction / Q000502:physiology; D014945:Wound Healing; D000097794:Kalinin
D015815:Cell Adhesion Molecules; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007797:Laminin; D019869:Phosphatidylinositol 3-Kinases; D000097794:Kalinin; C095567:laminin alpha 3