Abstract
CC(A/T)(6)GG or serum response elements represent a common regulatory motif important for regulating the expression of many smooth muscle-specific genes. They are multifunctional elements that bind serum response factor (SRF) and are important for serum induction of genes, expression of muscle-specific genes, and differentiation of vascular smooth muscle cells. In the current study, a yeast two-hybrid screen was used to identify proteins from mouse intestine that interact with SRF. A novel homeodomain-containing transcription factor, called Barx2b, was identified that specifically interacts with SRF and promotes the DNA binding activity of SRF. Northern blotting, RNase protection analysis, and Western blotting revealed that Barx2b mRNA and protein are expressed in several smooth muscle-containing tissues, as well as in skeletal muscle and brain. In vitro binding studies using bacterial fusion proteins revealed that the DNA-binding domain of SRF interacts with a region of Barx2b located amino-terminal of the homeobox domain. The results of these studies support the hypothesis that interaction of SRF with different homeodomain-containing proteins may play a critical role in determining the cell-specific functions of SRF.
Highlights
Analysis of several smooth muscle-specific genes has, far, failed to identify any smooth muscle-restricted transcription factors that control their expression
Results show that Barx2b is a novel homeodomain-containing protein that interacts with serum response factor (SRF) and increases the affinity of SRF for DNA
The enhancement of DNA binding by Phox1/Mhox was found to be primarily kinetic in vitro, and additional cellular proteins such as TFII-I are required in vivo to stabilize the SRF-homeodomain complexes [24]
Summary
Analysis of several smooth muscle-specific genes has, far, failed to identify any smooth muscle-restricted transcription factors that control their expression (reviewed in Ref. 1). For example the smooth muscle ␣-actin gene contains several CArG elements that are required for transcriptional activity; the endogenous gene or a reporter gene containing a 1063-bp fragment of the promoter is not induced by serum. A truncated 191-bp ␣-actin promoter fragment is induced by serum [15], suggesting that within this single gene, the function of SRF bound to CArG elements is dependent on interactions with factors that bind to other elements within the gene. These studies show that a novel homeodomain-containing transcription factor, Barx2b, interacts with SRF and promotes the DNA binding activity of SRF
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