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Divergent gene regulation and growth effects by NF-κB in epithelial and mesenchymal cells of human skin

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Abstract

NF-κB regulates normal and pathological processes, including neoplasia, in a tissue-context-dependent manner. In skin, NF-κB is implicated in epidermal homeostasis as well as in the pathogenesis of squamous cell carcinoma; however, its function in the underlying mesenchymal dermis has been unclear. To gain insight into NF-κB roles in these two adjacent cutaneous tissue compartments, NF-κB effects on expression of 12 435 genes were determined in epidermal keratinocytes and dermal fibroblasts. Although NF-κB induced proinflammatory and antiapoptotic genes in both settings, it exhibited divergent effects on growth regulatory genes. In keratinocytes, but not in fibroblasts, NF-κB induced p21CIP1, which was sufficient to inhibit growth of both cell types. Levels of growth inhibitory factor (GIF), in contrast, were increased by NF-κB in both settings but inhibited growth only in keratinocytes. These findings indicate that transcription factors such as NF-κB can program tissue-selective effects via both differential target gene induction as well as by inducing common targets that exert differing effects depending on cellular lineage.

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Acknowledgements

We thank G Nolan, H Blau and J Crabtree for presubmission review. We also thank N Rice for c-Rel cDNA, U Siebenlist for RelB cDNA, G Nabel and N Perkins for p52/p100 and RelA/p65 cDNAs, S Memet and A Israel for NF-κB-lacZ reporter mice.

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  1. Program in Epithelial Biology, Stanford University School of Medicine, Stanford, 94305, CA, USA

    Kaede Hinata, Adam M Gervin, Y Jennifer Zhang & Paul A Khavari

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  1. Kaede Hinata
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  2. Adam M Gervin
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  3. Y Jennifer Zhang
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  4. Paul A Khavari
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Correspondence to Paul A Khavari.

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Hinata, K., Gervin, A., Jennifer Zhang, Y. et al. Divergent gene regulation and growth effects by NF-κB in epithelial and mesenchymal cells of human skin. Oncogene 22, 1955–1964 (2003). https://doi.org/10.1038/sj.onc.1206198

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