Identification of novel AP-1 target genes in fibroblasts regulated during cutaneous wound healing

Florin, Lore; Hummerich, Lars; Dittrich, B.; Kokocinski, Felix; Wrobel, Gunnar; Gack, Sabine; Schorpp-Kistner, Marina; Werner, Sabine; Hahn, Meinhard; Lichter, Peter; Szabowski, Axel; Angel, Peter

doi:10.1038/sj.onc.1207938

Cited by 60 publications

(57 citation statements)

References 61 publications

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“…Recently, global transcriptom profiling and complex molecular genetics have been used to provide additional understanding of c-Jun (Florin et al, 2004;Wolter et al, 2008;Biddie et al, 2011;Li et al, 2011). It is anticipated that future work, based on sophisticated genetic and molecular approaches, will be instrumental to delineate the multifaceted regulation and functions of c-Jun in vivo.…”

Section: Resultsmentioning

confidence: 99%

c-Jun, at the crossroad of the signaling network

2011

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Section: Resultsmentioning

confidence: 99%

c-Jun, at the crossroad of the signaling network

2011

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“…fibroblasts, the heparin-binding factor pleiotrophin (PTN; also known as heparin-binding growth-associated molecule, HB-GAM) and the stromal cell-derived factor-1 [SDF-1; also known as chemokine (C-X-C motif) ligand 12, CXCL12], which we identified in a microarray screen designed to elucidate the diversity of JUN-dependent genes involved in mesenchymal-epithelial interactions during cutaneous wound repair (Florin et al, 2004). We determined the expression of both factors in murine skin in vivo during tissue homeostasis and wound healing and analysed their functional impact on keratinocyte growth in vitro.…”

Section: Introductionmentioning

confidence: 99%

Increased keratinocyte proliferation by JUN-dependent expression of PTN and SDF-1 in fibroblasts

Florin

Maas‐Szabowski

Werner

et al. 2005

Journal of Cell Science

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107

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In skin, fibroblasts of the connective tissue play a decisive role in epidermal homeostasis and repair by contributing to the regulation of keratinocyte proliferation and differentiation. The AP-1 transcription factor subunit JUN plays a crucial role in this mesenchymal-epithelial interplay by regulating the expression of two critical paracrine-acting cytokines, keratinocyte growth factor (KGF) and granulocyte-macrophage colony-stimulating factor (GM-CSF). We have performed gene expression profiling of wild-type and Jun–/– mouse embryonic fibroblasts to identify additional players involved in this complex network, and have found pleiotrophin (PTN) and the stromal cell-derived factor 1 (SDF-1) as novel JUN-regulated factors. Both cytokines are expressed by dermal fibroblasts in vivo, as shown by semi-quantitative RT-PCR and in situ hybridization on murine skin sections. Using a heterologous feeder layer co-culture system, we demonstrated that PTN and SDF-1 exert a mitogenic effect on primary human keratinocytes. Moreover, SDF-1-induced keratinocyte proliferation could be specifically inhibited by neutralizing antibodies against SDF-1 or its receptor, CXCR4. Consistent with its role in promoting keratinocyte growth, PTN was upregulated during cutaneous wound healing in vivo. Interestingly, co-cultivation with keratinocytes stimulated PTN expression but repressed SDF-1 production in fibroblasts, demonstrating the complexity of the paracrine regulatory cytokine networks that control skin homeostasis and regeneration.

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“…KGF/FGF-7 is one of the AP-1-regulated genes induced by the pro-inflammatory cytokines (14). However, KGF/FGF-7-mediated downstream signaling pathways are still unclear.…”

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confidence: 99%