Divergent Gene Regulation and Growth Effects by NF-kappa B in Epithelial and Mesenchymal Cells of Human Skin

Oncogene. 2003 Apr 3;22(13):1955-64. doi: 10.1038/sj.onc.1206198.

Abstract

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.

Publication types

  • Comparative Study

MeSH terms

  • Apoptosis / genetics
  • Cell Division / drug effects
  • Cell Lineage
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins / biosynthesis
  • Cyclins / genetics
  • Epithelial Cells / metabolism
  • Fibroblasts / cytology
  • Fibroblasts / metabolism*
  • Gene Expression Profiling
  • Gene Expression Regulation*
  • Humans
  • I-kappa B Proteins / genetics
  • I-kappa B Proteins / physiology
  • Inflammation / genetics
  • Keratinocytes / cytology
  • Keratinocytes / metabolism*
  • Mesoderm / cytology
  • Mesoderm / metabolism
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / genetics
  • NF-kappa B / physiology*
  • Nerve Tissue Proteins / biosynthesis
  • Nerve Tissue Proteins / genetics
  • Organ Specificity
  • Recombinant Fusion Proteins / physiology
  • Skin / cytology*
  • Skin / metabolism
  • Transcription, Genetic
  • Transcriptional Activation

Substances

  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • I-kappa B Proteins
  • NF-kappa B
  • NFKBIA protein, human
  • Nerve Tissue Proteins
  • Recombinant Fusion Proteins
  • growth inhibitory factor
  • NF-KappaB Inhibitor alpha