Calgranulins S100A8 and S100A9 are negatively regulated by glucocorticoids in a c-Fos-dependent manner and overexpressed throughout skin carcinogenesis.
The two calgranulins S100A8 and S100A9 were found to be differentially expressed at sites of acute and chronic inflammation. Here we have employed the phorbol ester-induced multistage skin carcinogenesis protocol in mice to determine the expression of both genes in inflamed skin and in skin tumors. We show that expression is coordinately induced by the phorbol ester TPA in epithelial cells as well as infiltrating leukocytes. By comparing S100A8 and S100A9 mRNA levels in wild type and c-Fos deficient mice (c-fos(-/-)) we found that expression is negatively regulated by c-Fos/AP-1. Glucocorticoids, which exhibit potent anti-inflammatory and anti-tumor promoting activities repressed TPA-mediated S100A8 and S100A9 induction in wild type, but not in c-fos(-/-) mice, thus identifying both genes as the first examples of AP-1 target genes whose repression of TPA-induced transcription by glucocorticoids depends on c-Fos. Finally, we show that enhanced expression is not restricted to the initial TPA-induced inflammatory response but is observed at all stages of skin carcinogenesis. These data identify S100A8 and S100A9 as novel, tumor-associated genes and may point to an as yet unrecognized function of both genes in the development of epithelial skin tumors.
Gebhardt
Christoffer
C
Deutsches Krebsforschungszentrum, Division of Signal Transduction and Growth Control, 69120 Heidelberg, Germany.
Breitenbach
Ute
U
Tuckermann
Jan Peter
JP
Dittrich
Bernd Thilo
BT
Richter
Karl Hartmut
KH
Angel
Peter
P
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000943:Antigens, Differentiation / Q000096:biosynthesis* / Q000235:genetics; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D002118:Calcium / Q000502:physiology; D002135:Calcium-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D040501:Calgranulin A; D040502:Calgranulin B; D002273:Carcinogens / Q000494:pharmacology / Q000633:toxicity; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D018450:Disease Progression; D003875:Drug Eruptions / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016762:Genes, fos; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D010212:Papilloma / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D016760:Proto-Oncogene Proteins c-fos / Q000172:deficiency / Q000502:physiology*; D009418:S100 Proteins / Q000096:biosynthesis* / Q000235:genetics; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D013047:Specific Pathogen-Free Organisms; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology / Q000633:toxicity; D018808:Transcription Factor AP-1 / Q000502:physiology*
D000893:Anti-Inflammatory Agents; D000943:Antigens, Differentiation; D018931:Antineoplastic Agents, Hormonal; D002135:Calcium-Binding Proteins; D040501:Calgranulin A; D040502:Calgranulin B; D002273:Carcinogens; D016760:Proto-Oncogene Proteins c-fos; D009418:S100 Proteins; D018808:Transcription Factor AP-1; D003907:Dexamethasone; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium