Visit our Expo - Redox and Inflammation signaling 2012

AP-1-dependent gene expression in skin remodelling and tumourigenesis
Peter Angel
Deutsches Krebsforschungszentrum, Division Signal Transduction and Growth Control
(A100), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
The transcription factor AP-1, which is composed of members of the Fos, Jun and ATF
protein families participates in physiological and pathophysiological processes due to its
central role as a cellular switch of genetic programs in response to extracellular signals. The
distinct expression pattern of AP-1 subunits in the skin, the loss of chemically induced
carcinogenesis in AP-1 compromised mice, and the large number of putative AP-1 target
genes in epidermal cells, indicate that AP-1 members play a pivotal role in epidermal
organisation, skin homeostasis and tumourigenesis (1, 2). We have employed a heterologous
organotypic coculture system containing fibroblasts from c-Jun or JunB-deficient mice to
identify trans-regulatory activities of c-Jun and JunB in the paracrine interaction between
keratinocytes and dermal fibroblasts (3). Large-scale expression profiling of these cultures
revealed novel AP-1 target genes in fibroblasts including cytokines, growth factors and
chemoattractants (4). Mice lacking the AP-1 member JunB in skin exhibit defects in wound
healing, which is associated with aberrant expression of these newly identified target genes
(5). The mouse skin was also the model of choice to study the regulation and function of AP-1
subunits in tumourigenesis in vivo (1). Upon combination of the well-established chemically
induced mouse model of epithelial skin tumours and expression profiling we have identified a
novel signalling pathway activating AP-1, which is initiated by S100A8 and S100 A9, two
members of the S100 family of Ca2+ binding proteins (6), which are also upregulated in a c-
Jun/JunB-dependent mouse model of human psoriasis (7). Both genes are also overexpressed
in human epithelial tumours of the skin and other organs, suggesting an important role of this
pathway in tumour progression and metastasis.
1. Angel, P., Szabowski, A., and Schorpp-Kistner M. (2001). Function and regulation of AP-1 subunits in skin
physiology and pathology. Oncogene 20, 2413-23
2. Hess, J., Angel, P. and Schorpp-Kistner, M. (2004) Functions of AP-1 subunits: Quarrel and Harmony among
Siblings. J. Cell Sci 117:5965-73
3. Szabowski, A., Maas-Szabowski, N., Andrecht, S., Kolbus, A., Schorpp-Kistner, M., Fusenig, N.E. and
Angel, P. (2000) c-Jun and JunB antagonistically control cytokine regulated mesenchymal-epidermal interaction
in skin.” Cell 103, 745-55
4. Florin, L., Hummerich, L., Dittrich, B., Kokocinski, F., Wrobel, G., Gack, S., Schorpp-Kistner, M., Werner,
S., Hahn, M., Lichter, P., Szabowski, A., Angel, P. (2004) Identification of novel AP-1 target genes in
fibroblasts regulated during cutaneous wound healing. Oncogene 23:7005-17
5. Florin, L., Knebel, J., Zigrino, P., Vonderstrass, B., Mauch, C., Schorpp-Kistner, M., Szabowski, A. and
Angel P. (2005) Delayed wound healing and epidermal hyperproliferation in mice lacking JunB in the skin. J Inv
Dermatol, in press
6. Gebhardt, C., Breitenbach, U., Tuckermann, J. P., Dittrich, B. T., Richter, K. H., and Angel, P. (2002).
Calgranulins S100A8 and S100A9 are negatively regulated by glucocorticoids in a c-Fos-dependent manner and
overexpressed throughout skin carcinogenesis. Oncogene 21, 4266-4276.
7. Zenz R., Eferl R., Kenner L., Florin L., Hummerich, Mehic D., Scheuch H., Angel P., Tschachler E. and
Wagner, E.F. (2005) Psoriasis-like skin disease and arthritis caused by inducible epidermal deletion of Jun
proteins. Nature (2005) 437, 369-75
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