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J. Biol. Chem., Vol. 278, Issue 20, 18506-18513, May 16, 2003
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From the Departments of Sonic hedgehog (Shh), a vertebrate
homologue of the Drosophila segment-polarity gene hedgehog,
has been reported to play an important role during normal development
of various tissues. Abnormal activities of Shh signaling pathway have
been implicated in tumorigenesis such as basal cell carcinomas and
medulloblastomas. Here we show that Shh signaling negatively regulates
prostatic epithelial ductal morphogenesis. In organotypic cultures of
developing rat prostates, Shh inhibited cell proliferation and promoted
differentiation of luminal epithelial cells. The expression pattern of
Shh and its receptors suggests a paracrine mechanism of action. The Shh receptors Ptc1
(Patched1)
and Ptc2 were found to be expressed in prostatic stromal cells adjacent
to the epithelium, where Shh itself was produced. This paracrine
model was confirmed by co-culturing the developing prostate in the
presence of stromal cells transfected with a vector expressing a
constitutively active form of Smoothened, the real effector
of the Shh signaling pathway. Furthermore, expression of activin A and
TGF-
Inhibition of Epithelial Ductal Branching in the
Prostate by Sonic Hedgehog Is Indirectly Mediated by Stromal Cells*
§,§¶,,
,
Molecular Oncology,
Pathology, and ** Molecular Biology, Genentech,
Inc., South San Francisco, California 94080
1 that were shown previously to inhibit prostatic epithelial
branching was up-regulated following Shh treatment in the organotypic
cultures. Taken together, these results suggest that Shh
negatively regulates prostatic ductal branching indirectly by acting on
the surrounding stromal cells, at least partly via up-regulating
expression of activin A and TGF-1.
*
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: Dept. of
Molecular Oncology, MS #72, Genentech, Inc., 1 DNA Way, South San
Francisco, CA 94080. Tel.: 650-225-8101; Fax: 650-225-6240; E-mail:
gao@gene.com.
Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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