scholarly journals LSD1 modulates stress-evoked transcription of immediate early genes and emotional behavior

2016 ◽  
Vol 113 (13) ◽  
pp. 3651-3656 ◽  
Author(s):  
Francesco Rusconi ◽  
Barbara Grillo ◽  
Luisa Ponzoni ◽  
Silvia Bassani ◽  
Emanuela Toffolo ◽  
...  
Keyword(s):  
Psychosocial Stress ◽  
Serum Response Factor ◽  
Dominant Negative ◽  
Emotional Behavior ◽  
Behavioral Changes ◽  
Lysine Specific Demethylase ◽  
Neuronal Gene ◽  
Response To Stress ◽  
Early Growth Response 1 ◽  
Serum Response

Behavioral changes in response to stressful stimuli can be controlled via adaptive epigenetic changes in neuronal gene expression. Here we indicate a role for the transcriptional corepressor Lysine-Specific Demethylase 1 (LSD1) and its dominant-negative splicing isoform neuroLSD1, in the modulation of emotional behavior. In mouse hippocampus, we show that LSD1 and neuroLSD1 can interact with transcription factor serum response factor (SRF) and set the chromatin state of SRF-targeted genes early growth response 1 (egr1) and c-fos. Deletion or reduction of neuroLSD1 in mutant mice translates into decreased levels of activating histone marks at egr1 and c-fos promoters, dampening their psychosocial stress-induced transcription and resulting in low anxiety-like behavior. Administration of suberoylanilide hydroxamine to neuroLSD1KO mice reactivates egr1 and c-fos transcription and restores the behavioral phenotype. These findings indicate that LSD1 is a molecular transducer of stressful stimuli as well as a stress-response modifier. Indeed, LSD1 expression itself is increased acutely at both the transcriptional and splicing levels by psychosocial stress, suggesting that LSD1 is involved in the adaptive response to stress.

scholarly journals Four isoforms of serum response factor that increase or inhibit smooth-muscle-specific promoter activity

2000 ◽  
Vol 345 (3) ◽  
pp. 445-451 ◽  
Author(s):  
Paul R. KEMP ◽  
James C. METCALFE
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Serum Response Factor ◽  
Muscle Cells ◽  
Dominant Negative ◽  
C2c12 Cells ◽  
Specific Gene ◽  
Response Factor ◽  
Transactivation Domain ◽  
Serum Response

Serum response factor (SRF) is a key transcriptional activator of the c-fos gene and of muscle-specific gene expression. We have identified four forms of the SRF coding sequence, SRF-L (the previously identified form), SRF-M, SRF-S and SRF-I, that are produced by alternative splicing. The new forms of SRF lack regions of the C-terminal transactivation domain by splicing out of exon 5 (SRF-M), exons 4 and 5 (SRF-S) and exons 3, 4 and 5 (SRF-I). SRF-M is expressed at similar levels to SRF-L in differentiated vascular smooth-muscle cells and skeletal-muscle cells, whereas SRF-L is the predominant form in many other tissues. SRF-S expression is restricted to vascular smooth muscle and SRF-I expression is restricted to the embryo. Transfection of SRF-L and SRF-M into C2C12 cells showed that both forms are transactivators of the promoter of the smooth-muscle-specific gene SM22α, whereas SRF-I acted as a dominant negative form of SRF.

scholarly journals Dominant Negative Murine Serum Response Factor: Alternative Splicing within the Activation Domain Inhibits Transactivation of Serum Response Factor Binding Targets

1999 ◽  
Vol 19 (7) ◽  
pp. 4582-4591 ◽  
Author(s):  
Narasimhaswamy S. Belaguli ◽  
Wei Zhou ◽  
Thuy-Hanh T. Trinh ◽  
Mark W. Majesky ◽  
Robert J. Schwartz
Keyword(s):  
Dna Binding ◽  
Serum Response Factor ◽  
Smooth Muscles ◽  
Dominant Negative ◽  
C2c12 Cells ◽  
Luciferase Reporter ◽  
Response Factor ◽  
Activation Domain ◽  
Alternatively Spliced ◽  
Serum Response

ABSTRACT Primary transcripts encoding the MADS box superfamily of proteins, such as MEF2 in animals and ZEMa in plants, are alternatively spliced, producing several isoformic species. We show here that murine serum response factor (SRF) primary RNA transcripts are alternatively spliced at the fifth exon, deleting approximately one-third of the C-terminal activation domain. Among the different muscle types examined, visceral smooth muscles have a very low ratio of SRFΔ5 to SRF. Increased levels of SRFΔ5 correlates well with reduced smooth muscle contractile gene activity within the elastic aortic arch, suggesting important biological roles for differential expression of SRFΔ5 variant relative to wild-type SRF. SRFΔ5 forms DNA binding-competent homodimers and heterodimers. SRFΔ5 acts as a naturally occurring dominant negative regulatory mutant that blocks SRF-dependent skeletal α-actin, cardiac α-actin, smooth α-actin, SM22α, and SRF promoter-luciferase reporter activities. Expression of SRFΔ5 interferes with differentiation of myogenic C2C12 cells and the appearance of skeletal α-actin and myogenin mRNAs. SRFΔ5 repressed the serum-induced activity of the c-fos serum response element. SRFΔ5 fused to the yeast Gal4 DNA binding domain displayed low transcriptional activity, which was complemented by overexpression of the coactivator ATF6. These results indicate that the absence of exon 5 might be bypassed through recruitment of transcription factors that interact with extra-exon 5 regions in the transcriptional activating domain. The novel alternatively spliced isoform of SRF, SRFΔ5, may play an important regulatory role in modulating SRF-dependent gene expression.

scholarly journals Recruitment of the tinman homolog Nkx-2.5 by serum response factor activates cardiac alpha-actin gene transcription.

1996 ◽  
Vol 16 (11) ◽  
pp. 6372-6384 ◽  
Author(s):  
C Y Chen ◽  
R J Schwartz
Keyword(s):  
Dna Binding ◽  
Serum Response Factor ◽  
Binding Activity ◽  
Dominant Negative ◽  
Actin Gene ◽  
Response Factor ◽  
Dna Binding Activity ◽  
Actin Promoter ◽  
Alpha Actin ◽  
Serum Response

We recently showed that the cardiogenic homeodomain factor Nkx-2.5 served as a positive acting accessory factor for serum response factor (SRF) and that together they provided strong transcriptional activation of the cardiac alpha-actin promoter, depending upon intact serum response elements (SREs) (C. Y. Chen, J. Croissant, M. Majesky, S. Topouz, T. McQuinn, M. J. Frankovsky, and R. J. Schwartz, Dev. Genet. 19:119-130, 1996). As shown here, Nkx-2.5 and SRF collaborated to activate the endogenous murine cardiac alpha-actin gene in 10T1/2 fibroblasts by a mechanism in which SRF recruited Nkx-2.5 to the alpha-actin promoter. Activation of a truncated promoter consisting of the proximal alpha-actin SRE1 occurred even when Nkx-2.5 DNA-binding activity was blocked by a point mutation in the third helix of its homeodomain. Investigation of protein-protein interactions showed that Nkx-2.5 was bound to SRF in the absence of DNA in soluble protein complexes retrieved from cardiac myocyte nuclei but could also be detected in coassociated binding complexes on the proximal SRE1. Recruitment of Nkx-2.5 to an SRE depended upon SRF DNA-binding activity and was blocked by the dominant negative SRFpm1 mutant, which allowed for dimerization of SRF monomers but prevented DNA binding. Interactive regions shared by Nkx-2.5 and SRF were mapped to N-terminal/helix I and helix II/helix III regions of the Nkx-2.5 homeodomain and to the N-terminal extension of the MADS box. Our study suggests that physical association between Nkx-2.5 and SRF is one way that cardiac specified genes are activated in cardiac cell lineages.

scholarly journals Novel Transcription Coactivator Complex Containing Activating Signal Cointegrator 1

2002 ◽  
Vol 22 (14) ◽  
pp. 5203-5211 ◽  
Author(s):  
Dong-Ju Jung ◽  
Hee-Sook Sung ◽  
Young-Wha Goo ◽  
Hyun Mi Lee ◽  
Ok Ku Park ◽  
...  
Keyword(s):  
Nuclear Receptors ◽  
Serum Response Factor ◽  
Ectopic Expression ◽  
Nuclear Factor Κb ◽  
Dominant Negative ◽  
Mutant Form ◽  
Negative Effects ◽  
Direct Binding ◽  
Serum Response

ABSTRACT Human activating signal cointegrator 1 (hASC-1) was originally isolated as a transcriptional coactivator of nuclear receptors. Here we report that ASC-1 exists as a steady-state complex associated with three polypeptides, P200, P100, and P50, in HeLa nuclei; stimulates transactivation by serum response factor (SRF), activating protein 1 (AP-1), and nuclear factor κB (NF-κB) through direct binding to SRF, c-Jun, p50, and p65; and relieves the previously described transrepression between nuclear receptors and either AP-1 or NF-κB. Interestingly, ectopic expression of Caenorhabditis elegans ASC-1 (ceASC-1), an ASC-1 homologue that binds P200 and P100, like hASC-1, while weakly interacting only with p65, in HeLa cells appears to replace endogenous hASC-1 from the hASC-1 complex and exerts potent dominant-negative effects on AP-1, NF-κB, and SRF transactivation. In addition, neutralization of endogenous P50 by single-cell microinjection of a P50 antibody inhibits AP-1 transactivation; the inhibition is relieved by coexpression of wild-type P50, but not of P50ΔKH, a mutant form that does not interact with P200. Overall, these results suggest that the endogenous hASC-1 complex appears to play an essential role in AP-1, SRF, and NF-κB transactivation and to mediate the transrepression between nuclear receptors and either AP-1 or NF-κB in vivo.

scholarly journals Sarcomeres regulate murine cardiomyocyte maturation through MRTF-SRF signaling

2020 ◽  
Vol 118 (2) ◽  
pp. e2008861118
Author(s):  
Yuxuan Guo ◽  
Yangpo Cao ◽  
Blake D. Jardin ◽  
Isha Sethi ◽  
Qing Ma ◽  
...  
Keyword(s):  
Nuclear Localization ◽  
Serum Response Factor ◽  
Mitochondrial Genes ◽  
Dominant Negative ◽  
Response Factor ◽  
Strongly Correlated ◽  
Transcriptional Dysregulation ◽  
Transcriptional Changes ◽  
Major Bottleneck ◽  
Serum Response

The paucity of knowledge about cardiomyocyte maturation is a major bottleneck in cardiac regenerative medicine. In development, cardiomyocyte maturation is characterized by orchestrated structural, transcriptional, and functional specializations that occur mainly at the perinatal stage. Sarcomeres are the key cytoskeletal structures that regulate the ultrastructural maturation of other organelles, but whether sarcomeres modulate the signal transduction pathways that are essential for cardiomyocyte maturation remains unclear. To address this question, here we generated mice with cardiomyocyte-specific, mosaic, and hypomorphic mutations of α-actinin-2 (Actn2) to study the cell-autonomous roles of sarcomeres in postnatal cardiomyocyte maturation. Actn2 mutation resulted in defective structural maturation of transverse-tubules and mitochondria. In addition, Actn2 mutation triggered transcriptional dysregulation, including abnormal expression of key sarcomeric and mitochondrial genes, and profound impairment of the normal progression of maturational gene expression. Mechanistically, the transcriptional changes in Actn2 mutant cardiomyocytes strongly correlated with those in cardiomyocytes deleted of serum response factor (SRF), a critical transcription factor that regulates cardiomyocyte maturation. Actn2 mutation increased the monomeric form of cardiac α-actin, which interacted with the SRF cofactor MRTFA and perturbed its nuclear localization. Overexpression of a dominant-negative MRTFA mutant was sufficient to recapitulate the morphological and transcriptional defects in Actn2 and Srf mutant cardiomyocytes. Together, these data indicate that Actn2-based sarcomere organization regulates structural and transcriptional maturation of cardiomyocytes through MRTF-SRF signaling.

scholarly journals RhoA GTPase and Serum Response Factor Control Selectively the Expression of MyoD without Affecting Myf5 in Mouse Myoblasts

1998 ◽  
Vol 9 (7) ◽  
pp. 1891-1902 ◽  
Author(s):  
Gilles Carnac ◽  
Michael Primig ◽  
Magali Kitzmann ◽  
Philippe Chafey ◽  
David Tuil ◽  
...  
Keyword(s):  
Gene Expression ◽  
G Proteins ◽  
Transcriptional Activation ◽  
Serum Response Factor ◽  
Muscle Differentiation ◽  
Dominant Negative ◽  
Response Factor ◽  
Rhoa Protein ◽  
Myod Gene ◽  
Serum Response

MyoD and Myf5 belong to the family of basic helix-loop-helix transcription factors that are key operators in skeletal muscle differentiation. MyoD and Myf5 genes are selectively activated during development in a time and region-specific manner and in response to different stimuli. However, molecules that specifically regulate the expression of these two genes and the pathways involved remain to be determined. We have recently shown that the serum response factor (SRF), a transcription factor involved in activation of both mitogenic response and muscle differentiation, is required for MyoD gene expression. We have investigated here whether SRF is also involved in the control of Myf5 gene expression, and the potential role of upstream regulators of SRF activity, the Rho family G-proteins including Rho, Rac, and CDC42, in the regulation of MyoD and Myf5. We show that inactivation of SRF does not alter Myf5 gene expression, whereas it causes a rapid extinction of MyoD gene expression. Furthermore, we show that RhoA, but not Rac or CDC42, is also required for the expression of MyoD. Indeed, blocking the activity of G-proteins using the general inhibitor lovastatin, or more specific antagonists of Rho proteins such as C3-transferase or dominant negative RhoA protein, resulted in a dramatic decrease of MyoD protein levels and promoter activity without any effects on Myf5 expression. We further show that RhoA-dependent transcriptional activation required functional SRF in C2 muscle cells. These data illustrate that MyoD and Myf5 are regulated by different upstream activation pathways in which MyoD expression is specifically modulated by a RhoA/SRF signaling cascade. In addition, our results establish the first link between RhoA protein activity and the expression of a key muscle regulator.

Increased expression of alternatively spliced dominant-negative isoform of SRF in human failing hearts

2002 ◽  
Vol 282 (4) ◽  
pp. H1521-H1533 ◽  
Author(s):  
Francesca J. Davis ◽  
Madhu Gupta ◽  
Steven M. Pogwizd ◽  
Emile Bacha ◽  
Valluan Jeevanandam ◽  
...  
Keyword(s):  
Heart Failure ◽  
Serum Response Factor ◽  
Dominant Negative ◽  
Full Length ◽  
Cardiac Gene Expression ◽  
Cardiac Gene ◽  
Muscle Genes ◽  
Alternatively Spliced ◽  
Muscle Gene ◽  
Serum Response

Serum response factor (SRF) has been shown to play a key role in cardiac cell growth and muscle gene regulation. To understand the role of SRF in heart failure, we compared its expression pattern between control and failing human heart samples. Western blot analysis of control samples showed expression of four different isoforms of SRF, with ∼67-kDa full-length SRF being the predominant isoform. Interestingly, in failing hearts we found robust expression of a low-molecular-mass (∼52 kDa) SRF isoform, accompanied by decreased expression of full-length SRF. By RT-PCR and Southern blot analyses, we characterized this ∼52-kDa SRF isoform as being encoded by an alternatively spliced form of SRF lacking exons 4 and 5 of the SRF primary RNA transcript (SRF-Δ4,5 isoform). We cloned SRF-Δ4,5 cDNA and showed that overexpression of this isoform into cells inhibits SRF-dependent activation of cardiac muscle genes. These results suggest that expression of SRF-Δ4,5 in failing hearts may in part contribute to impaired cardiac gene expression and consequently to the pathogenesis of heart failure.

scholarly journals Increased Myosin Light Chain Kinase Expression in Hypertension: Regulation by Serum Response Factor via an Insertion Mutation in the Promoter

2006 ◽  
Vol 17 (9) ◽  
pp. 4039-4050 ◽  
Author(s):  
Yoo-Jeong Han ◽  
Wen-Yang Hu ◽  
Olga Chernaya ◽  
Nenad Antic ◽  
Lianzhi Gu ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Myosin Light Chain Kinase ◽  
Promoter Activity ◽  
Myosin Light Chain ◽  
Serum Response Factor ◽  
Vascular Diseases ◽  
Dominant Negative ◽  
Response Factor ◽  
Carg Box ◽  
Serum Response

Regulation of gene transcription in vascular smooth muscle cells (VSMCs) by serum response factor (SRF) plays a crucial role in vascular development and in the pathophysiology of vascular diseases. Nevertheless, the regulation of specific genes by SRF in vascular diseases is poorly understood. Therefore, we investigated the regulation of smooth muscle myosin light chain kinase (smMLCK) by using spontaneously hypertensive rats (SHR) as an experimental model. We found that smMLCK expression in blood vessels increases during the development of hypertension and is always greater in blood vessels from SHR compared with normotensive rats. Analysis of the DNA sequences of the promoters isolated from SHR and normotensive rats revealed that SHR contain a 12-base pair insertion adjacent to the CArG box. This insertion increases SRF binding to the CArG box and positively regulates SRF-dependent promoter activity. The increase in smMLCK expression was blocked by dominant-negative SRF, dominant-negative Ras, or antisense oligonucleotides to ERK. In vivo, inhibiting MEK decreased smMLCK expression and blood pressure in SHR partly by decreasing SRF binding to the smMLCK promoter. These data provide novel insight into the regulation of smMLCK expression at the molecular level and demonstrate the importance of SRF in regulating smMLCK promoter activity in SHR.

Arteriogenesis: A focus on signal transduction cascades and transcription factors

2007 ◽  
Vol 98 (11) ◽  
pp. 940-943 ◽  
Author(s):  
Elisabeth Deindl
Keyword(s):  
Signal Transduction ◽  
Transcription Factors ◽  
Molecular Mechanisms ◽  
Serum Response Factor ◽  
Rho Kinase ◽  
Early Growth Response ◽  
Collateral Artery ◽  
Early Growth Response 1 ◽  
Serum Response ◽  
Increased Blood Flow

SummaryIn recent years intensive investigations have been performed to unravel the molecular mechanisms of collateral artery growth (arteriogenesis), a process designed by nature to compensate the devastating consequences of major arterial occlusions. Currently, a variety of gene products as well as signal transduction pathways involved in arteriogenesis have been identified. However, it is still not clear how the progression of cellular signals evoked by an increased blood flow and therefore mechanical stress proceeds. Literature research identified the transcription factors early growth response-1 (Egr-1) as well as serum response factor (SRF) and myocardin-related transcription factors (MRTFs) as liaisons connecting the key pathways of arteriogenesis, i.e.the Rho-kinase pathway and the MEK/ERK pathway, with each other as well as with downstream genes.

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