The single-strand DNA/RNA-binding protein, Purβ, regulates serum response factor (SRF)-mediated cardiac muscle gene expressionThis paper is one of a selection of papers published in this Special Issue, entitled The Cellular and Molecular Basis of Cardiovascular Dysfunction, Dhalla 70th Birthday Tribute.

2007 ◽  
Vol 85 (3-4) ◽  
pp. 349-359 ◽  
Author(s):  
Madhu Gupta ◽  
Vithida Sueblinvong ◽  
Mahesh P. Gupta
Keyword(s):  
Gene Expression ◽  
Cardiac Muscle ◽  
Rna Binding ◽  
Serum Response Factor ◽  
Single Strand ◽  
Specific Gene ◽  
Response Factor ◽  
Repressive Effect ◽  
Muscle Gene ◽  
Serum Response

Single-strand DNA-binding proteins, Purα and Purβ, play a role in cell growth and differentiation by modulating both transcriptional and translational controls of gene expression. We have previously characterized binding of Purα and Purβ proteins to a purine-rich negative regulatory (PNR) element of the rat cardiac α-myosin heavy chain (MHC) gene that controls cardiac muscle specificity. In this study we investigated the role of upstream sequences of the α-MHC promoter in Purβ-mediated gene repression. In the transient transfection analysis overexpression of Purβ revealed a negative regulatory effect on serum response factor (SRF)-dependent α-MHC and α-skeletal actin expression in muscle cell background. Contrary, in nonmuscle cells, Purβ showed no repressive effect. The results obtained from gel-shift assays demonstrated a sequence specific competitive binding of Purβ to the minus strand of the SRF-binding, CArG box sequences of different muscle genes, but not to the SRF-binding, SRE sequences of the c-fos gene. These element-specific associations of Purβ with muscle CArG boxes may, in part, explain why muscle gene expression is downregulated in disease states in which Purβ levels are elevated. This data also provide a mechanistic distinction between muscle CArG boxes and nonmuscle serum response element (SRE) sequences in terms of their affinity to bind to SRF and their ability to regulate cell-specific gene expression.

scholarly journals New Role for Serum Response Factor in Postnatal Skeletal Muscle Growth and Regeneration via the Interleukin 4 and Insulin-Like Growth Factor 1 Pathways

2006 ◽  
Vol 26 (17) ◽  
pp. 6664-6674 ◽  
Author(s):  
Claude Charvet ◽  
Christophe Houbron ◽  
Ara Parlakian ◽  
Julien Giordani ◽  
Charlotte Lahoute ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Growth Factor ◽  
Serum Response Factor ◽  
Muscle Growth ◽  
Interleukin 4 ◽  
Specific Gene ◽  
Response Factor ◽  
Insulin Like Growth Factor ◽  
Serum Response

ABSTRACT Serum response factor (SRF) is a crucial transcriptional factor for muscle-specific gene expression. We investigated SRF function in adult skeletal muscles, using mice with a postmitotic myofiber-targeted disruption of the SRF gene. Mutant mice displayed severe skeletal muscle mass reductions due to a postnatal muscle growth defect resulting in highly hypotrophic adult myofibers. SRF-depleted myofibers also failed to regenerate following injury. Muscles lacking SRF had very low levels of muscle creatine kinase and skeletal alpha-actin (SKA) transcripts and displayed other alterations to the gene expression program, indicating an overall immaturity of mutant muscles. This loss of SKA expression, together with a decrease in beta-tropomyosin expression, contributed to myofiber growth defects, as suggested by the extensive sarcomere disorganization found in mutant muscles. However, we observed a downregulation of interleukin 4 (IL-4) and insulin-like growth factor 1 (IGF-1) expression in mutant myofibers which could also account for their defective growth and regeneration. Indeed, our demonstration of SRF binding to interleukin 4 and IGF-1 promoters in vivo suggests a new crucial role for SRF in pathways involved in muscle growth and regeneration.

scholarly journals Different regulatory sequences control creatine kinase-M gene expression in directly injected skeletal and cardiac muscle.

1993 ◽  
Vol 13 (2) ◽  
pp. 1264-1272 ◽  
Author(s):  
C K Vincent ◽  
A Gualberto ◽  
C V Patel ◽  
K Walsh
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Creatine Kinase ◽  
Cardiac Muscle ◽  
Serum Response Factor ◽  
Sequence Motif ◽  
Regulatory Sequences ◽  
Response Factor ◽  
Specific Expression ◽  
Serum Response

Regulatory sequences of the M isozyme of the creatine kinase (MCK) gene have been extensively mapped in skeletal muscle, but little is known about the sequences that control cardiac-specific expression. The promoter and enhancer sequences required for MCK gene expression were assayed by the direct injection of plasmid DNA constructs into adult rat cardiac and skeletal muscle. A 700-nucleotide fragment containing the enhancer and promoter of the rabbit MCK gene activated the expression of a downstream reporter gene in both muscle tissues. Deletion of the enhancer significantly decreased expression in skeletal muscle but had no detectable effect on expression in cardiac muscle. Further deletions revealed a CArG sequence motif at position -179 within the promoter that was essential for cardiac-specific expression. The CArG element of the MCK promoter bound to the recombinant serum response factor and YY1, transcription factors which control expression from structurally similar elements in the skeletal actin and c-fos promoters. MCK-CArG-binding activities that were similar or identical to serum response factor and YY1 were also detected in extracts from adult cardiac muscle. These data suggest that the MCK gene is controlled by different regulatory programs in adult cardiac and skeletal muscle.

scholarly journals Physiological Control of Smooth Muscle-specific Gene Expression through Regulated Nuclear Translocation of Serum Response Factor

2000 ◽  
Vol 275 (39) ◽  
pp. 30387-30393 ◽  
Author(s):  
Blanca Camoretti-Mercado ◽  
Hong-W. Liu ◽  
Andrew J. Halayko ◽  
Sean M. Forsythe ◽  
John W. Kyle ◽  
...  
Keyword(s):  
Gene Expression ◽  
Smooth Muscle ◽  
Serum Response Factor ◽  
Nuclear Translocation ◽  
Specific Gene ◽  
Response Factor ◽  
Physiological Control ◽  
Specific Gene Expression ◽  
Serum Response

scholarly journals KLF3 Regulates Muscle-Specific Gene Expression and Synergizes with Serum Response Factor on KLF Binding Sites

2010 ◽  
Vol 30 (14) ◽  
pp. 3430-3443 ◽  
Author(s):  
Charis L. Himeda ◽  
Jeffrey A. Ranish ◽  
Richard C. M. Pearson ◽  
Merlin Crossley ◽  
Stephen D. Hauschka
Keyword(s):  
Binding Sites ◽  
Serum Response Factor ◽  
Control Element ◽  
Specific Gene ◽  
Response Factor ◽  
Gene Promoters ◽  
Muscle Creatine Kinase ◽  
Muscle Genes ◽  
Muscle Gene ◽  
Serum Response

ABSTRACT This study identifies KLF3 as a transcriptional regulator of muscle genes and reveals a novel synergistic interaction between KLF3 and serum response factor (SRF). Using quantitative proteomics, KLF3 was identified as one of several candidate factors that recognize the MPEX control element in the Muscle creatine kinase (MCK) promoter. Chromatin immunoprecipitation analysis indicated that KLF3 is enriched at many muscle gene promoters (MCK, Myosin heavy chain IIa, Six4, Calcium channel receptor α-1, and Skeletal α-actin), and two KLF3 isoforms are upregulated during muscle differentiation. KLF3 and SRF physically associate and synergize in transactivating the MCK promoter independently of SRF binding to CArG motifs. The zinc finger and repression domains of KLF3 plus the MADS box and transcription activation domain of SRF are implicated in this synergy. Our results provide the first evidence of a role for KLF3 in muscle gene regulation and reveal an alternate mechanism for transcriptional regulation by SRF via its recruitment to KLF binding sites. Since both factors are expressed in all muscle lineages, SRF may regulate many striated- and smooth-muscle genes that lack known SRF control elements, thus further expanding the breadth of the emerging CArGome.

scholarly journals Different regulatory sequences control creatine kinase-M gene expression in directly injected skeletal and cardiac muscle

1993 ◽  
Vol 13 (2) ◽  
pp. 1264-1272
Author(s):  
C K Vincent ◽  
A Gualberto ◽  
C V Patel ◽  
K Walsh
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Creatine Kinase ◽  
Cardiac Muscle ◽  
Serum Response Factor ◽  
Sequence Motif ◽  
Regulatory Sequences ◽  
Response Factor ◽  
Specific Expression ◽  
Serum Response

Regulatory sequences of the M isozyme of the creatine kinase (MCK) gene have been extensively mapped in skeletal muscle, but little is known about the sequences that control cardiac-specific expression. The promoter and enhancer sequences required for MCK gene expression were assayed by the direct injection of plasmid DNA constructs into adult rat cardiac and skeletal muscle. A 700-nucleotide fragment containing the enhancer and promoter of the rabbit MCK gene activated the expression of a downstream reporter gene in both muscle tissues. Deletion of the enhancer significantly decreased expression in skeletal muscle but had no detectable effect on expression in cardiac muscle. Further deletions revealed a CArG sequence motif at position -179 within the promoter that was essential for cardiac-specific expression. The CArG element of the MCK promoter bound to the recombinant serum response factor and YY1, transcription factors which control expression from structurally similar elements in the skeletal actin and c-fos promoters. MCK-CArG-binding activities that were similar or identical to serum response factor and YY1 were also detected in extracts from adult cardiac muscle. These data suggest that the MCK gene is controlled by different regulatory programs in adult cardiac and skeletal muscle.

scholarly journals Myocardin Sumoylation Transactivates Cardiogenic Genes in Pluripotent 10T1/2 Fibroblasts

2006 ◽  
Vol 27 (2) ◽  
pp. 622-632 ◽  
Author(s):  
Jun Wang ◽  
AnKang Li ◽  
ZhiGao Wang ◽  
XinHua Feng ◽  
Eric N. Olson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Posttranslational Modification ◽  
Serum Response Factor ◽  
Gene Activity ◽  
Response Factor ◽  
Dependent Manner ◽  
Sumoylation Site ◽  
Sumo Modification ◽  
Muscle Gene ◽  
Serum Response

ABSTRACT Myocardin, a serum response factor (SRF)-dependent cofactor, is a potent activator of smooth muscle gene activity but a poor activator of cardiogenic genes in pluripotent 10T1/2 fibroblasts. Posttranslational modification of GATA4, another myocardin cofactor, by sumoylation strongly activated cardiogenic gene activity. Here, we found that myocardin's activity was strongly enhanced by SUMO-1 via modification of a lysine residue primarily located at position 445 and that the conversion of this residue to arginine (K445R) impaired myocardin transactivation. PIAS1 was involved in governing myocardin activity via its E3 ligase activity that stimulated myocardin sumoylation on an atypical sumoylation site(s) and by its physical association with myocardin. Myocardin initiated the expression of cardiac muscle-specified genes, such as those encoding cardiac α-actin and α-myosin heavy chain, in an SRF-dependent manner in 10T1/2 fibroblasts, but only in the presence of coexpressed SUMO-1/PIAS1. Thus, SUMO modification acted as a molecular switch to promote myocardin's role in cardiogenic gene expression.

Cardiomyopathy in transgenic mice with cardiac-specific overexpression of serum response factor

2001 ◽  
Vol 280 (4) ◽  
pp. H1782-H1792 ◽  
Author(s):  
Xiaomin Zhang ◽  
Gohar Azhar ◽  
Jianyuan Chai ◽  
Pamela Sheridan ◽  
Koichiro Nagano ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Cardiac Muscle ◽  
Serum Response Factor ◽  
Interstitial Fibrosis ◽  
Weight Ratio ◽  
Heart Weight ◽  
Cardiomyocyte Hypertrophy ◽  
Response Factor ◽  
Serum Response

Serum response factor (SRF), a member of the MCM1, agamous, deficiens, SRF (MADS) family of transcriptional activators, has been implicated in the transcriptional control of a number of cardiac muscle genes, including cardiac α-actin, skeletal α-actin, α-myosin heavy chain (α-MHC), and β-MHC. To better understand the in vivo role of SRF in regulating genes responsible for maintenance of cardiac function, we sought to test the hypothesis that increased cardiac-specific SRF expression might be associated with altered cardiac morphology and function. We generated transgenic mice with cardiac-specific overexpression of the human SRF gene. The transgenic mice developed cardiomyopathy and exhibited increased heart weight-to-body weight ratio, increased heart weight, and four-chamber dilation. Histological examination revealed cardiomyocyte hypertrophy, collagen deposition, and interstitial fibrosis. SRF overexpression altered the expression of SRF-regulated genes and resulted in cardiac muscle dysfunction. Our results demonstrate that sustained overexpression of SRF, in the absence of other stimuli, is sufficient to induce cardiac change and suggest that SRF is likely to be one of the downstream effectors of the signaling pathways involved in mediating cardiac hypertrophy.

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