© 1999 American Heart Association, Inc.
Vascular Biology |
Similarities and Differences in Smooth Muscle 
-Actin Induction by TGF-ß in Smooth Muscle Versus Non–Smooth Muscle Cells
From the Department of Molecular Physiology and Biological Physics, University of Virginia Health Sciences Center, Charlottesville (P.J.A., G.K.O.); the Franz-Volhard Clinic, Charité at the Humboldt University of Berlin, Berlin, Germany (M.B.H.); and the Department of Medicine, University of Cambridge, Addenbrookes Hospital, Cambridge, UK (P.J.A.).
Correspondence to Paul J. Adam or Gary K. Owens, Department of Molecular Physiology and Biological Physics, Box 449, University of Virginia Health Sciences Center, Charlottesville, VA 22908. E-mail gko{at}virginia.edu
Abstract—Transforming growth
factor-ß (TGF-ß) has been shown to stimulate smooth muscle (SM)
-actin expression in smooth muscle cells (SMCs) and non-SMCs. We
previously demonstrated that the 2 CArG boxes A and B and a novel
TGF-ß control element (TCE) located within the first 125 bp of the SM
-actin promoter were required for TGF-ß inducibility of SM
-actin in SMCs. The aims of the present study were (1) to
determine whether the TCE exhibits SMC specificity or contributes to
TGF-ß induction of SM -actin expression in non-SMCs (ie,
endothelial cells and fibroblasts) and (2) to determine
whether TGF-ß can induce expression of multiple TCE-containing SMC
differentiation marker genes, such as SM22, h1 calponin,
and SM myosin heavy chain (SM MHC) in non-SMCs. Results of transient
transfection assays demonstrated that mutation of CArG A, CArG B, or
the TCE within a 125-bp promoter context completely abolished TGF-ß
inducibility of SM -actin in endothelial cells and
fibroblasts. However, in contrast to observations in SMCs, inclusion of
regions upstream from -155 completely repressed TGF-ß responsiveness
in non-SMCs. Electrophoretic mobility shift assays showed that TGF-ß
enhanced binding of a serum response factor to the CArG elements and
the binding of an as-yet-unidentified factor to the TCE in
endothelial cells and fibroblasts, but to a much lesser
extent compared with SMCs. TGF-ß also stimulated expression of the
SMC differentiation marker SM22 in non-SMCs. However, in contrast to
SMCs, TGF-ß did not induce expression of h1 calponin and
SM MHC in non-SMCs. In summary, these results suggest a conserved role
for CArG A, CArG B, and the TCE in TGF-ß–induced expression of SM
-actin in SMCs and non-SMCs that is modified by a complex interplay
of positive- and negative-acting cis elements in a
cell-specific manner. Furthermore, observations that TGF-ß stimulated
expression of several early but not late differentiation markers in
non-SMCs indicate that TGF-ß alone is not sufficient to induce
transdifferentiation of non-SMCs into SMCs.
Key Words: smooth muscle -actin • transforming growth factor-ß • smooth muscle cells • non–smooth muscle cells
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