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SERUM RESPONSE FACTOR; SRF

SERUM RESPONSE FACTOR; SRF

Alternative titles; symbolsC-FOS SERUM RESPONSE ELEMENT-BINDING FACTORHGNC Approved Gene Symbol: SRFCytogenetic location: 6p21.1 Genomic coordinates (GRCh38)...

Alternative titles; symbols

  • C-FOS SERUM RESPONSE ELEMENT-BINDING FACTOR

HGNC Approved Gene Symbol: SRF

Cytogenetic location: 6p21.1 Genomic coordinates (GRCh38): 6:43,171,268-43,181,505 (from NCBI)

▼ Description
Homodimerized SRF proteins bind to the CArG box consensus sequence found in the control regions of numerous serum-inducible and muscle-specific genes (Spencer et al., 1999).

▼ Cloning and Expression
The serum response element (SRE) is a DNA sequence required for the transient transcription of a number of genes in response to growth factor or mitogen stimulation. Norman et al. (1988) isolated cDNA clones encoding serum response factor (SRF), a ubiquitous nuclear protein that binds to the SRE. Two mRNAs of 4.5 and 2.9 kb are produced from the gene by alternative polyadenylation. The longest open reading frame encodes a protein of 508 amino acids. The SRF gene is highly evolutionarily conserved and was detectable by Southern blotting in Drosophila and Xenopus DNA. In cultured cells, SRF transcription is transiently increased following serum stimulation. When the cDNA is expressed in vitro the SRF protein formed complexes indistinguishable from those produced with HeLa cell SRF, as judged by DNA binding specificity and the ability to promote SRE-dependent transcription. SRF binds DNA as a dimer, and the DNA binding/dimerization domain of the protein shares strong sequence similarity to the yeast regulatory proteins MCM1 and ARG80.

By in situ hybridization and expression of a reporter gene driven by the Srf promoter, Barron et al. (2005) found Srf expression was largely restricted to cardiac and skeletal muscle tissues during mouse embryonic development.

▼ Mapping
The International Radiation Hybrid Mapping Consortium mapped the SRF gene to chromosome 6 (RH46608).

▼ Gene Function
Using a yeast 1-hybrid assay, Spencer et al. (1999) found that human SRF bound to rat Ssrp1 (604328). The interaction was mediated through the MADS box of SRF and amino acids 489 to 542 of Ssrp1, which are immediately adjacent to the HMG domain. Ssrp1 itself did not bind a DNA CArG box, but it did dramatically increase the DNA binding activity of SRF, resulting in synergistic transcriptional activation of native and artificial SRF-dependent promoters. Spencer et al. (1999) concluded that SSRP1 is a coregulator of SRF-dependent transcription in mammalian cells.

Chang et al. (2003) examined cardiac SRF protein levels from 23 patients with end-stage heart failure, 10 of whom were supported by left ventricular assist devices (LVAD), and 7 normal hearts. Full-length SRF was markedly reduced and processed into 55- and 32-kD subfragments in the 13 unsupported failing hearts. SRF was intact in normal samples, whereas samples from the hearts of the 10 LVAD patients showed minimal SRF fragmentation. Specific antibodies to N- and C-terminal SRF sequences and site-directed mutagenesis revealed 2 alternative caspase-3 (600636) cleavage sites. Expression of the 32-kD N-terminal SRF fragment in myogenic cells inhibited the transcriptional activity of alpha-actin (102610) gene promoters by 50 to 60%. Chang et al. (2003) concluded that caspase-3 activation in heart failure sequentially cleaves SRF and generates a truncated SRF that appears to function as a dominant-negative transcription factor. They suggested that caspase-3 activation may be reversible in the failing heart with ventricular unloading.

Smooth muscle cells switch between differentiated and proliferative phenotypes in response to extracellular cues. SRF activates genes involved in smooth muscle differentiation and proliferation by recruiting muscle-restricted cofactors, such as the transcriptional coactivator myocardin (MYOCD; 606127), and ternary complex factors (TCFs) of the ETS-domain family, respectively. Wang et al. (2004) showed that growth signals repress smooth muscle genes by triggering the displacement of myocardin from SRF by ELK1 (311040), a TCF that acts as a myogenic repressor. The opposing influences of myocardin and ELK1 on smooth muscle gene expression are mediated by structurally related SRF-binding motifs that compete for a common docking site on SRF. A mutant smooth muscle promoter, retaining responsiveness to myocardin and SRF but defective in TCF binding, directed ectopic transcription in the embryonic heart, demonstrating a role for TCFs in suppression of smooth muscle gene expression in vivo. Wang et al. (2004) concluded that growth and developmental signals modulate smooth muscle gene expression by regulating the association of SRF with antagonistic cofactors.

Barron et al. (2005) found the expression of mouse Srf was activated by Tip60 (HTATIP; 601409), Tbx2 (600747), and Tbx5 (601620), and activity required the 3-prime UTR of Srf, which contains many combinations of full and half palindromic T-box sites. Srf transactivation was blocked by Tip60 mutants in which either the histone acetyltransferase domain was inactivated or the zinc finger protein- binding domain was excised.

In vascular smooth muscle cells (VSMC) isolated from AD (104300) patients with CAA (605714), Bell et al. (2009) found an association between beta-amyloid (104760) deposition and increased expression of SRF and myocardin compared to controls. Further studies indicated the MYOCD upregulated SRF and generated a beta-amyloid nonclearing phenotype through transactivation of SREBP2 (600481), which downregulates LRP1 (107770), a key beta-amyloid clearance receptor. SRF silencing led to increased beta-amyloid clearance. Hypoxia stimulated SRF/MYOCD expression in human cerebral VSMCs and in animal models of AD. Bell et al. (2009) suggested that SRF and MYOCD function as a transcriptional switch, controlling beta-amyloid cerebrovascular clearance and progression of AD.

▼ Animal Model
Niu et al. (2005) noted that Srf-null mouse embryos fail to gastrulate and form mesoderm, and aggregates of Srf-null embryonic stem cells fail to express myogenic alpha-actins (see 102540), Sm22-alpha (TAGLN; 600818) and myocardin, and do not form beating cardiac myocytes. Niu et al. (2005) found that cardiac-specific ablation of Srf resulted in embryonic lethality due to cardiac insufficiency during chamber maturation. Reduced cell survival was also concomitant with increased apoptosis, reduced cell number, and reduced expression of atrial natriuretic factor (108780), and cardiac, skeletal (102610), and smooth muscle alpha-actin transcripts.

Li et al. (2005) found that mice with skeletal muscle-specific Srf deletion formed muscle fibers that failed to undergo hypertrophic growth after birth. Mutant mice died during the perinatal period from severe skeletal muscle hypoplasia. Mice expressing a dominant-negative Mrtfa (MKL1; 606078) mutant showed a similar myopathic phenotype, suggesting that SRF- and myocardin-related transcription factors control skeletal muscle growth and maturation.

Franco et al. (2008) found that Srf expression was restricted to endothelial cells of small vessels, such as capillaries, in mouse embryo. Endothelial cell-specific Srf deletion led to aneurysms and hemorrhages from embryonic day 11.5 and lethality at embryonic day 14.5. Mutant embryos presented a reduced capillary density and defects in endothelial cell migration, with fewer numbers of filopodia in tip cells and endothelial cells showing defects in actin polymerization and intercellular junctions. Srf was essential for expression of VE-cadherin (CDH5; 601120) and beta-actin (ACTB; 102630) in endothelial cells both in vivo and in vitro, and knockdown of Srf in endothelial cells impaired Vegf (192240)- and Fgf (see 131220)-induced in vitro angiogenesis. Franco et al. (2008) concluded that SRF plays an important role in sprouting angiogenesis and small vessel integrity.

Tags: 6p21.1