Divergent gene regulation and growth effects by NF-kappa B in epithelial and mesenchymal cells of human skin.
NF-kappa B regulates normal and pathological processes, including neoplasia, in a tissue-context-dependent manner. In skin, NF-kappa B 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-kappa B roles in these two adjacent cutaneous tissue compartments, NF-kappa B effects on expression of 12 435 genes were determined in epidermal keratinocytes and dermal fibroblasts. Although NF-kappa B induced proinflammatory and antiapoptotic genes in both settings, it exhibited divergent effects on growth regulatory genes. In keratinocytes, but not in fibroblasts, NF-kappa B induced p21(CIP1), which was sufficient to inhibit growth of both cell types. Levels of growth inhibitory factor (GIF), in contrast, were increased by NF-kappa B in both settings but inhibited growth only in keratinocytes. These findings indicate that transcription factors such as NF-kappa B 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.
Hinata
Kaede
K
Program in Epithelial Biology, Stanford University School of Medicine, CA 94305, USA.
Gervin
Adam M
AM
Jennifer Zhang
Y
Y
Khavari
Paul A
PA
D017209:Apoptosis / Q000235:genetics; D002455:Cell Division / Q000187:drug effects; D019070:Cell Lineage; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000502:physiology; D007249:Inflammation / Q000235:genetics; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism*; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism; D000090023:Metallothionein 3; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000235:genetics / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D009928:Organ Specificity; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012867:Skin / Q000166:cytology* / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D020672:I-kappa B Proteins; D000090023:Metallothionein 3; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D009419:Nerve Tissue Proteins; D011993:Recombinant Fusion Proteins; D000072000:NF-KappaB Inhibitor alpha