Role of serum response factor in the pathogenesis of disease

Abstract

Serum response factor (SRF) is a ubiquitously expressed transcription factor that binds to a DNA cis element known as the CArG box, which is found in the proximal regulatory regions of over 200 experimentally validated target genes. Genetic deletion of SRF is incompatible with life in a variety of animals from different phyla. In mice, loss of SRF throughout the early embryo results in gastrulation defects precluding analyses in individual organ systems. Genetic inactivation studies using conditional or inducible promoters directing the expression of the bacteriophage Cre recombinase have shown a vital role for SRF in such cellular processes as contractility, cell migration, synaptic activity, inflammation, and cell survival. A growing number of experimental and human diseases are associated with changes in SRF expression, suggesting that SRF has a role in the pathogenesis of disease. This review summarizes data from experimental model systems and human pathology where SRF expression is either deliberately or naturally altered. Genomic DNA is a quaternary code comprising proteincoding and non-protein-coding sequences. While the protein-coding sequences are well-defined and increasingly understood, we are only beginning to elucidate the hidden information within the vast landscape of the non-proteincoding sequences. The field of comparative genomics has facilitated the identification of transcription factor-binding sites (TFBS) and microRNAs (miRs), which, aside from repetitive DNA sequences, are among the more easily decipherable non-protein-coding sequences in the human genome. Together, TFBS and miRs have essential roles in cell fate determination and cellular homeostasis of most life forms. Sequence variations (eg, single-nucleotide polymorphisms, SNPs) in the TFBS, miRs, and miR target sequences alter gene/protein expression and thus disturb homeostasis leading to disease. 1-4 A major imperative, therefore, is decoding the non-protein-coding genome relating to gene regulation to gain a full understanding of how DNA-binding transcription factors and the estimated one million or more TFBS direct normal biological processes.Serum response factor (SRF) is the founding member of the MADS-box family of transcription factors 5 and is one of the best understood DNA-binding proteins in the human proteome. The DNA-binding properties of SRF and its molecular cloning were first defined in the laboratory of Richard Treisman. 6,7 SRF has relatively low intrinsic transcriptional activity, but its interaction with over 60 cofactors confers strong transactivation potential in a cell-and context-specific manner. At least two major signaling pathways converge upon SRF to direct the programs of gene expression. 8,9 The classic pathway involves growth factor stimulation and mitogen-activated protein kinase signaling leading to the phosphorylation of the SRF cofactor, ELK1, and the activation of growth-related genes. 10,11 The second regulatory pathway occurs through Rho-dependent changes in actin dynamics. 12 In this pathway, si...

SRF selectively controls tip cell invasive behavior in angiogenesis

“…The pruned gene (blistered) in Drosophila encodes the serum response factor (SRF), an evolutionarily conserved transcription factor that regulates the expression of genes through binding to a CArG box [CC(A/T) 6 GG] (Miano et al, 2007). SRF function appears to be particularly important in processes involving cell migration, including Drosophila tracheal morphogenesis, dorsal root ganglion terminal innervation and angiogenesis (Franco and Li, 2009;Miano, 2010). SRF transcriptional output is regulated mainly by its cooperation with two divergent co-factor families: the ternary complex factors ELK1, ELK3 (NET) and ELK4 (SAP1), which are under control of the MAPK signaling cascade (Buchwalter et al, 2004); and the myocardin-related transcription factors (MRTFs) MRTF-A (MKL1, MAL) and MRTF-B (MKL2), which are regulated by the actin polymerization state (Miralles et al, 2003;Vartiainen et al, 2007).…”

Muscle Creatine Kinase Deficiency Triggers Both Actin Depolymerization and Desmin Disorganization by Advanced Glycation End Products in Dilated Cardiomyopathy

“…The MADS box transcription factor serum response factor (SRF) is a major regulator of genes encoding contractile proteins, notably all muscle actin isoforms, but also of genes involved in energy transfer like muscle creatine kinase (MCK) or in calcium homeostasis like NCX1 (4). SRF is activated by cytokines, growth factors, and G-coupled receptors, which are known to play a major role in cardiac remodeling.…”

Gastric Ulcer Healing – Role of Serum Response Factor

“…Among many transcription factors involved in ulcer healing, Serum response factor (SRF) is the master regulator. SRF is ubiquitously expressed in every type of tissue and its targeted genes take up nearly 1% of our entire genome (Sun et al, 2006;Miano, 2010). SRF can be activated by growth factors, cytokines and chemokines, and in return, activated SRF can direct expressions of these molecules to heal ulcers in a precisely organized manner.…”

“…These studies link SRF to the main cause of peptic ulcer. In addition to peptic ulcer, SRF has also been associated with other digestive functions and abnormalities, which has been reviewed elsewhere (Modak & Chai, 2010;Miano, 2010). Fig.…”