Model of functional cardiac aging: young adult mice with mild overexpression of serum response factor

Azhar

Journal of Biological Chemistry

et al. 2004

Self Cite

The transcription factor serum response factor (SRF) plays an important role in the regulation of a variety of cardiac genes during development and during adult aging. A novel SRF cofactor, herein called p49/STRAP, for SRF-dependent transcription regulation-associated protein, was recently identified in our laboratory. This protein interacted mainly with the transcriptional activation domain of the SRF protein and was found to bind to SRF or to the complex of SRF and another cofactor, such as myocardin or Nkx2.5. The expression of p49/ STRAP affected the promoter activity of SRF target genes in a non-uniform manner. For example, p49 activated MLC2v and cardiac actin promoters when it was co-transfected with SRF, but it repressed atrial natriuretic factor promoter activity, which was strongly induced by myocardin. The p49/STRAP mRNA was observed to be highly expressed in fetal, adult, and senescent human hearts, and also in hearts of young adult and old mice, suggesting that p49/STRAP may be an important SRF cofactor in the transcriptional regulation of mammalian cardiac muscle genes throughout the life span.

Section: P49/strap a New Srf Cofactormentioning

confidence: 98%

mentioning

confidence: 99%

Identification of a Novel Serum Response Factor Cofactor in Cardiac Gene Regulation

Azhar

Journal of Biological Chemistry

et al. 2004

Self Cite

Laboratory Investigation

“…42 A subsequent report showed that lower SRF expression induced a milder phenotype with evidence of accelerated cardiac aging in young transgenic mice. 43 Both studies concluded that overexpression of SRF elicits a heart failure phenotype. In this context, human heart failure was reported to show elevations of a natural dominant-negative form of SRF arising from alternative splicing.…”

Section: Srf and Cardiovascular System Disease Heartmentioning

confidence: 99%

Role of serum response factor in the pathogenesis of disease

Miano

2010

123

100

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 plays an important role in the regulation of smooth, skeletal, and cardiac muscle genes [5][6][7][8] during development and in adult life including aging. 9,10 Srf can be activated to promote transcription in response to extracellular signals that induce its association with specific cofactors. The 2 families of Srf cofactors are the TCF proteins (Elk1, SAP1, SAP2), 11 and the myocardin family of proteins that includes myocardin, megakaryoblastic leukemia 1 (Mkl1), and Mkl2.…”

Section: Introductionmentioning

confidence: 99%

Serum response factor is an essential transcription factor in megakaryocytic maturation

Halene

Gao²,

Hahn³

et al. 2010

Blood

IntroductionSerum response factor (Srf), a nearly ubiquitous transcription factor that is expressed in all hematopoietic cell types, is a founding member of the MCM1-agamous-deficiens-Srf (MADS) domain-containing family of transcription factors, and binds to so called CArG sites (CC/AT-rich/GG, with CCTTATATGG emerging as a major consensus sequence). 1 More than 200 CArG boxes control expression of more than 150 Srf target genes, including genes of the cytoskeleton as well as several immediateearly genes, for example the proto-oncogene c-fos, 2 and also bcl2, 3 whereby Srf participates in apoptosis, cell growth, differentiation, and cell-cycle regulation. Srf is a downstream target of many pathways; for example, the mitogen-activated protein kinase pathway that acts through the ternary complex factors (TCF) as well as Rho signaling, 4 which promotes actin polymerization. Srf plays an important role in the regulation of smooth, skeletal, and cardiac muscle genes 5-8 during development and in adult life including aging. 9,10 Srf can be activated to promote transcription in response to extracellular signals that induce its association with specific cofactors. The 2 families of Srf cofactors are the TCF proteins (Elk1, SAP1, SAP2), 11 and the myocardin family of proteins that includes myocardin, megakaryoblastic leukemia 1 (Mkl1), and Mkl2. 1,12,13 In some cell types, TCF proteins and Mkl1 compete for binding to Srf to activate or inhibit distinct transcription targets. 14,15 In Drosophila, Srf interaction with Mkl (MAL-D) promotes cytoskeletal strength during cellular migration. 16,17 In murine embryonic stem cells, Srf is crucial for actin cytoskeletal organization and focal adhesion assembly. 18 Murine embryos lacking Srf fail to form mesoderm and thus die early in development. 19 Prior work in our laboratory has focused on acute megakaryoblastic leukemia with the t(1;22) translocation, involving fusion between an RNA binding motif protein 15 (RBM15) and Mkl1. Mkl1 is known to act as a cofactor for Srf-mediated gene activation in muscle differentiation. 12,20 We have demonstrated a physiologic role for Mkl1 in megakaryopoiesis. 21 Mkl1 expression increases with normal megakaryocyte (Mk) differentiation, and promotes Mk polyploidization. Mkl1 knockout (KO) mice have normal hematopoietic stem cells and megakaryocyte-erythroid progenitors (Pre-Meg-E). However, there is a dramatic increase in the number of CD41 ϩ megakaryocytes with most of these having low (2N) ploidy. There is a significant decrease in the number of polyploid megakaryocytes and thrombocytopenia. Mkl1 requires Srf to enhance polyploidization during megakaryocytic differentiation. Based on these findings, we have examined the effects of the Mkl1 cofactor Srf in megakaryocyte development.We show, that Srf deletion specifically in the megakaryocytic lineage leads to macrothrombocytopenia, whereas bone marrow (BM) and spleen show significant accumulation of abnormal megakaryocytes. Examination of candidate Srf target genes reveals that several actin cyt...