Epiregulin, a novel member of the epidermal growth factor family, is an autocrine growth factor in normal human keratinocytes

Yuji Shirakata, Toshi Komurasaki, Hitoshi Toyoda, Yasushi Hanakawa, Kenshi Yamasaki, Sho Tokumaru, Koji Sayania, Koji Hashimoto

Research output: Contribution to journalArticlepeer-review

137 Citations (Scopus)

Abstract

Epiregulin is a new member of the epidermal growth factor (EGF) family purified from conditioned medium of NIH-3T3 clone T7. Some EGF family growth factors play essential roles in human keratinocytes in an autocrine manner. We show here that epiregulin is another autocrine growth factor for human keratinocytes. Epiregulin stimulated human keratinocyte proliferation under both subconfluent and confluent culture conditions in the absence of exogenous EGF family growth factors. Immunoprecipitation of [35S]methionine-labeled conditioned medium revealed a 5-kDa band corresponding to epiregulin. Northern blot analysis detected a 4.8-kilobase transcript of epiregulin, and the addition of epiregulin up-regulated epiregulin mRNA synthesis. Furthermore, an anti-epiregulin blocking antibody reduced DNA synthesis by 25%. Epiregulin up-regulated the mRNA levels of heparin-binding EGF-like growth factor (HB-EGF), amphiregulin, and TGF-α. In turn, the addition of EGF, HB-EGF, amphiregulin, and TGF-α increased epiregulin mRNA levels. These results demonstrate that epiregulin acts as an autocrine growth factor in human epidermal keratinocytes and is part of auto- and cross-induction mechanisms involving HB-EGF, amphiregulin, and TGF-α. The mRNA expression profile resulting from induction of differentiation with high calcium and fetal calf serum revealed the differential expression of epiregulin, HB-EGF, amphiregulin, and TGF-α in keratinocytes. This indicates that these four growth factors have distinct, non-redundant biological functions.

Original languageEnglish
Pages (from-to)5748-5753
Number of pages6
JournalJournal of Biological Chemistry
Volume275
Issue number8
DOIs
Publication statusPublished - 2000 Feb 25

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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