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J Biol Chem, Vol. 275, Issue 8, 5748-5753, February 25, 2000
From the Department of Dermatology, Ehime University School of
Medicine, Shitsukawa, Shigenobu-cho, Onsen-gun, Ehime 791-0295, Japan and the § Molecular Biology Laboratory, Medicinal
Research Laboratories, Taisho Pharmaceutical Co., Ltd., 403, Yoshino-cho, Omiyashi, Saitama 330-8530, Japan
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-
Epiregulin, a Novel Member of the Epidermal Growth Factor
Family, Is an Autocrine Growth Factor in Normal Human
Keratinocytes*
,
. In turn, the
addition of EGF, HB-EGF, amphiregulin, and TGF- 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-. 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- in keratinocytes. This indicates that these four growth factors
have distinct, non-redundant biological functions.
*
This work was supported by Grant-in-aid for Scientific
Research from the Ministry of Education, Science, Sports, and Culture of Japan (to Y. S. and K. H.).The costs of publication of this article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed. Tel.: +81-89-960-5350;
Fax: +81-89-960-5352; E-mail: shirakat@m.ehime-u.ac.jp.
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