Calgranulins S100A8 and S100A9 are negatively regulated by glucocorticoids in a c-Fos-dependent manner and overexpressed throughout skin carcinogenesis

TY - JOUR

T1 - Calgranulins S100A8 and S100A9 are negatively regulated by glucocorticoids in a c-Fos-dependent manner and overexpressed throughout skin carcinogenesis

AU - Gebhardt, Christoffer

AU - Breitenbach, Ute

AU - Tuckermann, Jan Peter

AU - Dittrich, Bernd Thilo

AU - Richter, Karl Hartmut

AU - Angel, Peter

PY - 2002/6/20

Y1 - 2002/6/20

N2 - 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.

AB - 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.

KW - Animals

KW - Anti-Inflammatory Agents

KW - Antigens, Differentiation

KW - Antineoplastic Agents, Hormonal

KW - Calcium

KW - Calcium-Binding Proteins

KW - Calgranulin A

KW - Calgranulin B

KW - Carcinogens

KW - Carcinoma, Squamous Cell

KW - Dexamethasone

KW - Disease Progression

KW - Drug Eruptions

KW - Female

KW - Gene Expression Regulation

KW - Gene Expression Regulation, Neoplastic

KW - Genes, fos

KW - Keratinocytes

KW - Leukocytes

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Inbred Strains

KW - Mice, Knockout

KW - Papilloma

KW - Protein Kinase C

KW - Proto-Oncogene Proteins c-fos

KW - S100 Proteins

KW - Skin Neoplasms

KW - Specific Pathogen-Free Organisms

KW - Tetradecanoylphorbol Acetate

KW - Transcription Factor AP-1

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1038/sj.onc.1205521

DO - 10.1038/sj.onc.1205521

M3 - SCORING: Journal article

C2 - 12082614

VL - 21

SP - 4266

EP - 4276

JO - ONCOGENE

JF - ONCOGENE

SN - 0950-9232

IS - 27

ER -