Key result
Coexpression of mNkx3-1 and serum response factor (SRF) was required to activate robust smooth muscle gamma-actin (SMGA) transcription via a novel complex element in the proximal promoter.
The smooth muscle gamma-actin gene is a novel target for Nkx3-1, and its promoter activity depends on cooperative interaction with serum response factor.
Hypothesis-generating for Nkx3-1 in vascular smooth muscle differentiation; human validation required before any clinical consideration.
An evolutionarily conserved vertebrate homologue of the Drosophila NK-3 homeodomain gene bagpipe, Nkx3-1, is expressed in vascular and visceral mesoderm-derived muscle tissues and may influence smooth muscle cell differentiation. Nkx3-1 was evaluated for mediating smooth muscle gamma-actin (SMGA) gene activity, a specific marker of smooth muscle differentiation. Expression of mNkx3-1 in heterologous CV-1 fibroblasts was unable to elicit SMGA promoter activity but required the coexpression of serum response factor (SRF) to activate robust SMGA transcription. A novel complex element containing a juxtaposed Nkx-binding site (NKE) and an SRF-binding element (SRE) in the proximal promoter region was found to be necessary for the Nkx3-1/SRF coactivation of SMGA transcription. Furthermore, Nkx3-1 and SRF associate through protein-protein interactions and the homeodomain region of Nkx3-1 facilitated SRF binding to the complex NKE.SRE. Mutagenesis of Nkx3-1 revealed an inhibitory domain within its C-terminal segment. In addition, mNkx3-1/SRF cooperative activity required an intact Nkx3-1 homeodomain along with the MADS box of SRF, which contains DNA binding and dimerization structural domains, and the contiguous C-terminal SRF activation domain. Thus, SMGA is a novel target for Nkx3-1, and the activity of Nkx3-1 on the SMGA promoter is dependent upon SRF.
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Carson et al. (2000) studied this question. mNkx3-1 and SRF coexpression vs. mNkx3-1 expression alone was evaluated on SMGA promoter activity and transcription. Coexpression of mNkx3-1 and serum response factor (SRF) was required to activate robust smooth muscle gamma-actin (SMGA) transcription via a novel complex element in the proximal promoter.
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