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J. Biol. Chem., Vol. 276, Issue 20, 17058-17062, May 18, 2001
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From Despite major advances in the
understanding of the intimate mechanisms of transforming growth
factor-
Identification of Novel TGF-
/Smad Gene Targets in Dermal
Fibroblasts using a Combined cDNA Microarray/Promoter
Transactivation Approach*
,¶
INSERM U532, Hôpital Saint-Louis, 75475 Paris, France and the § Department of Dermatology and
Cutaneous Biology, Thomas Jefferson University, Philadelphia
Pennsylvania
(TGF-) signaling through the Smad pathway, little
progress has been made in the identification of direct target genes. In
this report, using cDNA microarrays, we have focussed our attention
on the characterization of extracellular matrix-related genes rapidly
induced by TGF- in human dermal fibroblasts and attempted to
identify the ones whose up-regulation by TGF- is Smad-mediated. For
a gene to qualify as a direct Smad target, we postulated that it had to
meet the following criteria: (1) rapid (30 min) and significant
(at least 2-fold) elevation of steady-state mRNA levels upon
TGF- stimulation, (2) activation of the promoter by both exogenous
TGF- and co-transfected Smad3 expression vector, (3) up-regulation
of promoter activity by TGF- blocked by both dominant-negative Smad3
and inhibitory Smad7 expression vectors, and (4) promoter
transactivation by TGF- not possible in
Smad3
/ mouse embryo fibroblasts.
Using this stringent approach, we have identified COL1A2, COL3A1,
COL6A1, COL6A3, and tissue inhibitor of metalloproteases-1 as
definite TGF-/Smad3 targets. Extrapolation of this approach to other
extracellular matrix-related gene promoters also identified COL1A1 and
COL5A2, but not COL6A2, as novel Smad targets. Together, these results
represent a significant step toward the identification of novel,
early-induced Smad-dependent TGF- target genes in fibroblasts.
*
This work was supported by grants from the Association pour
la Recherche contre le Cancer (France; Subvention Libre 9058), INSERM,
France (APEX 4X809D), and Electricité de France (Service de
Radioprotection) (to A. M.) and by National Institutes of Health Grant
AR38912 (to M. L. C.).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.
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