Identification of novel AP-1 target genes in fibroblasts regulated during cutaneous wound healing.
Mesenchymal-epithelial interactions are increasingly considered to be of vital importance for epithelial homeostasis and regeneration. In skin, the transcription factor AP-1 was shown to be critically involved in the communication between keratinocytes and dermal fibroblasts. After skin injury, the release of IL-1 from keratinocytes induces the activity of the AP-1 subunits c-Jun and JunB in fibroblasts leading to a global change in gene expression. To identify AP-1 target genes in fibroblasts, which are involved in the process of cutaneous repair, we performed gene expression profiling of wild-type, c-jun- and junB-deficient fibroblasts in response to IL-1, mimicking the initial phase of wound healing. Using a 15K cDNA collection, over 1000 genes were found to be Jun-dependent and additional 300 clones showed IL-1 responsiveness. Combinatorial evaluation allowed for the dissection of the specific contribution of either AP-1 subunit to gene regulation. Besides previously identified genes that are involved in cutaneous repair, we have identified novel genes regulated during wound healing in vivo and showed their expression by fibroblasts on wound sections. The identification of novel Jun target genes should provide a basis for understanding the molecular mechanisms underlying mesenchymal-epithelial interactions and the critical contribution of AP-1 to tissue homeostasis and repair.
Florin
Lore
L
Division of Signal Transduction and Growth Control, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, Heidelberg D-69120, Germany.
Hummerich
Lars
L
Dittrich
Bernd Thilo
BT
Kokocinski
Felix
F
Wrobel
Gunnar
G
Gack
Sabine
S
Schorpp-Kistner
Marina
M
Werner
Sabine
S
Hahn
Meinhard
M
Lichter
Peter
P
Szabowski
Axel
A
Angel
Peter
P
D000818:Animals; D017931:DNA Primers; D005260:Female; D005347:Fibroblasts / Q000502:physiology*; D005784:Gene Amplification; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D016133:Polymerase Chain Reaction; D016755:Proto-Oncogene Proteins c-jun / Q000172:deficiency / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin; D018808:Transcription Factor AP-1 / Q000235:genetics*; D014945:Wound Healing / Q000235:genetics*
D017931:DNA Primers; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1