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Expression profiling of serum inducible genes identifies a subset of SRF target genes that are MKL dependent
1Department of Biological Sciences, Columbia University, New York, New York, USA. as814@columbia.edu
Background:
Serum Response Factor (SRF) is a transcription factor that is required for the expression of many genes including immediate early genes, cytoskeletal genes, and muscle-specific genes. SRF is activated in response to extra-cellular signals by its association with a diverse set of co-activators in different cell types. In the case of the ubiquitously expressed immediate early genes, the two sets of SRF binding proteins that regulate its activity are the TCF family of proteins that include Elk1, SAP1 and SAP2 and the myocardin-related MKL family of proteins that include MKL1 and MKL2 (also known as MAL, MRTF-A and -B and BSAC). In response to serum or growth factors these two classes of co-activators are activated by different upstream signal transduction pathways. However, it is not clear how they differentially activate SRF target genes.
Results:
In order to identify the serum-inducible SRF target genes that are specifically dependent on the MKL pathway, we have performed microarray experiments using a cell line that expresses dominant negative MKL1. This approach was used to identify SRF target genes whose activation is MKL-dependent. Twenty-eight of 150 serum-inducible genes were found to be MKL-dependent. The promoters of the serum-inducible genes were analyzed for SRF binding sites and other common regulatory elements. Putative SRF binding sites were found at a higher rate than in a mouse promoter database but were only identified in 12% of the serum-inducible promoters analyzed. Additional partial matches to the consensus SRF binding site were found at a higher than expected rate in the MKL-dependent gene promoters. The analysis for other common regulatory elements is discussed.
Conclusions:
These results suggest that a subset of immediate early and SRF target genes are activated by the Rho-MKL pathway. MKL may also contribute to the induction of other SRF target genes however its role is not essential, possibly due to other activation mechanisms such as MAPK phosphorylation of TCFs.
Insights
The Rho-MKL pathway specifically activates a subset of Serum Response Factor (SRF) target genes, revealing distinct regulatory mechanisms for immediate early genes. This highlights MKL
Area of Science:
- Molecular Biology
- Gene Regulation
- Cell Signaling
Background:
- Serum Response Factor (SRF) is a key transcription factor regulating immediate early, cytoskeletal, and muscle-specific genes.
- SRF activity is modulated by co-activators like TCFs and MKL proteins in response to extracellular signals.
- Differential activation of SRF target genes by these co-activators remains unclear.
Purpose of the Study:
- To identify serum-inducible SRF target genes specifically regulated by the MKL pathway.
- To elucidate the role of the Rho-MKL pathway in SRF-mediated gene expression.
Main Methods:
- Microarray experiments were conducted using a cell line expressing dominant-negative MKL1.
- Analysis of SRF binding sites and regulatory elements in the promoters of MKL-dependent genes.
Main Results:
- Twenty-eight out of 150 serum-inducible genes were identified as MKL-dependent.
- SRF binding sites were enriched in promoters of serum-inducible genes, with partial matches found more frequently in MKL-dependent promoters.
Conclusions:
- A subset of SRF target genes is activated via the Rho-MKL pathway.
- MKL's role in other SRF target genes may be non-essential, potentially due to alternative mechanisms like TCF phosphorylation.
