© 2000 American Heart Association, Inc.
Molecular Medicine |
Smooth Muscle 
-Actin CArG Elements Coordinate Formation of a Smooth Muscle Cell–Selective, Serum Response Factor–Containing Activation Complex
From the Department of Molecular Physiology and Biological Physics, University of Virginia Medical School, Charlottesville.
Correspondence to Gary K. Owens, PhD, Box 449, Health Sciences Center, University of Virginia, Charlottesville, VA 22908.
Abstract—Previous studies have
shown that multiple serum response factor (SRF)-binding CArG elements
were required for smooth muscle cell (SMC)-specific regulation of
smooth muscle (SM) 
-actin expression. However, a critical question
remains as to the mechanisms whereby a ubiquitously expressed
transcription factor such as SRF might contribute to SMC-specific
expression. The goal of the present study was to investigate the
hypothesis that SMC-selective expression of SM -actin is due at
least in part to (1) unique CArG flanking sequences that distinguish
the SM -actin CArGs from other ubiquitously expressed CArG-dependent
genes such as c-fos, (2) cooperative interactions
between CArG elements, and (3) SRF-dependent binding of SMC-selective
proteins to the CArG-containing regions of the promoter. Results
demonstrated that specific sequences flanking CArG B were important for
promoter activity in SMCs but not in bovine aortic
endothelial cells. We also provided evidence indicating
that the structural orientation between CArGs A and B was an important
determinant of promoter function. Electrophoretic mobility shift assays
and methylation interference footprinting demonstrated that a unique
SRF-containing complex formed that was selective for SMCs and,
furthermore, that this complex was probably stabilized by
protein-protein interactions and not by specific interactions with CArG
flanking sequences. Taken together, the results of these studies
provide evidence that SM -actin expression in SMCs is complex and
may involve the formation of a unique multiprotein initiation complex
that is coordinated by SRF complexes bound to multiple CArG
elements.
Key Words: serum response factor • smooth muscle -actin • CArG element
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