Differential Binding of an SRF/NK-2/MEF2 Transcription Factor Complex in Normal Versus Neoplastic Smooth Muscle Tissues

Phiel, Christopher J.; Gabbeta, Vijayalakshmi; Parsons, Linda M.; Rothblat, David S.; Harvey, Richard P.; McHugh, Kirk M.

doi:10.1074/jbc.m105826200

Cited by 34 publications

(30 citation statements)

References 74 publications

(125 reference statements)

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“…5). Prior studies indicate that normal cultured smooth muscle cells show a decrease in the expression of SRF as differentiation progresses from day 1 myoblast to day 10 myocyte (Phiel et al, 2001). In contrast to controls, Urp treatment of smooth muscle cells at 50, 100, and 100 pM resulted in the maintenance of high levels of SRF expression throughout the 10-day culture period, while 1,000 pM of Urp resulted in a pattern of SRF expression similar to that observed in controls (Fig.…”

Section: Urotensin Ii-related Peptidementioning

confidence: 57%

“…These findings are the first to suggest a potential connection between Urp expression and bladder smooth muscle development. Normal bladder smooth muscle development initiates with mesenchymal compaction around embryonic day 15 in mice, and appears unique in its spatial patterning from other smooth muscle tissues (Phiel et al, 2001;McHugh, 1995). In contrast, developing mgbϪ/Ϫ bladders show a lack of mesenchymal condensation resulting in independent clusters of differentiating smooth muscle myoblasts widely separated by regions of undifferentiated mesenchyme .…”

Section: Discussionmentioning

confidence: 99%

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Transcriptional profiling of the megabladder mouse: A unique model of bladder dysmorphogenesis

Singh¹,

Robinson²,

Ismail³

et al. 2007

Developmental Dynamics

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Recent studies in our lab identified a mutant mouse model of obstructive nephropathy designated mgb for megabladder. Homozygotic mgb mice (mgb؊/؊) develop lower urinary tract obstruction in utero due to a lack of bladder smooth muscle differentiation. This defect is the result of a random transgene insertion/translocation into chromosomes 11 and 16. Transcriptional profiling identified a significantly over-expressed cluster of gene products located on the translocated fragment of chromosome 16 including urotensin II-related peptide (Urp), which was shown to be preferentially over-expressed in developing mgb؊/؊ bladders. Pathway analysis of mgb microarray data indicated dysregulation of at least 60 gene products associated with smooth muscle development. In conclusion, the results of this study indicate that the molecular pathways controlling normal smooth muscle development are severely altered in mgb؊/؊ bladders, and provide the first evidence that Urp may play a critical role in bladder smooth muscle development. Developmental Dynamics 237:170 -186, 2008.

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Section: Urotensin Ii-related Peptidementioning

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Transcriptional profiling of the megabladder mouse: A unique model of bladder dysmorphogenesis

Singh¹,

Robinson²,

Ismail³

et al. 2007

Developmental Dynamics

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“…6 Several studies have shown a correlation between human cancer and elevated levels of SRF or SRF binding to CArG boxes. [99][100][101][102] Whether such increases in SRF are causative or merely reflective of human cancer is unclear. Recently, however, the liver-restricted miR-122 was shown to be attenuated in human hepatocellular carcinomas where SRF levels are elevated.…”

Section: Srf and Cancermentioning

confidence: 99%

Role of serum response factor in the pathogenesis of disease

Miano

2010

Laboratory Investigation

123

100

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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...

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“…Nkx2-5 belongs to the NK-2 homeobox family and has been implicated in myocardial development, in both cardiomyocytes and smooth muscle (76). In an in vitro model of smooth muscle differentiation, the promoter of the smooth muscle gamma isoactin gene has been shown to bind NK-2 and serum response factor in intestinal smooth muscle cells (57). In uterine smooth muscle cells myocyte enhancer factor 2 is also bound in this complex (57).…”

Section: Discussionmentioning

confidence: 99%

“…In an in vitro model of smooth muscle differentiation, the promoter of the smooth muscle gamma isoactin gene has been shown to bind NK-2 and serum response factor in intestinal smooth muscle cells (57). In uterine smooth muscle cells myocyte enhancer factor 2 is also bound in this complex (57). Previous studies have also reported the upregulation of several transcription factors associated with the transition from pregnant not-in-labor to laboring myometrium in rat, mouse and human (8,16,25,28,32,53,62,69).…”

Section: Discussionmentioning

confidence: 99%

Effects of combined progesterone and 17β-estradiol treatment on the transcriptome of cultured human myometrial smooth muscle cells

Chandran

Cairns

O’Brien

et al. 2016

Physiological Genomics

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Chandran S, Cairns MT, O'Brien M, O'Connell E, Mashayekhi K, Smith TJ. Effects of combined progesterone and 17␤-estradiol treatment on the transcriptome of cultured human myometrial smooth muscle cells. Physiol Genomics 48: 50 -61, 2016. First published November 3, 2015 doi:10.1152/physiolgenomics.00021.2015.-A transcriptomic analysis of cultured human uterine smooth muscle cells (hUtSMCs) was performed to examine gene expression profiles in smooth muscle in an environment containing the two major steroid hormones that regulate the human myometrium in physiological states associated with estrous, pregnancy, labor, and pathophysiological states such as leiomyoma and endometrial cancer. hUtSMCs were treated with progesterone (P4) and 17␤-estradiol (E2) individually and in combination, in the presence and absence of RU486 (mifepristone). Transcription of many genes was modulated in the presence of P4 or E2 alone, but almost six times more genes were transcriptionally modulated in the presence of the P4/E2 hormone combination. In total 796 annotated genes were significantly differentially expressed in the presence of both P4 and E2 relative to their expression in untreated cells. Functional withdrawal of P4 by addition of RU486 effectively reversed almost all transcriptional changes caused by P4/E2 treatment. Gene ontology analysis of differentially expressed genes revealed a strong association between P4/E2 treatment and downregulated expression of genes involved in cell communication, signal transduction, channel activity, inflammatory response, and differentiation. Upregulated processes included cell survival, gene transcription, steroid hormone biosynthesis, muscle development, insulin receptor signaling, and cell growth.progesterone; 17␤-estradiol; uterine smooth muscle cells; microarray; transcriptomics THE TWO STEROID HORMONES, estrogen and progesterone (P4), play vital roles in maintaining pregnancy and initiating labor (51) and more generally in myometrial physiology and contractility. P4 maintains uterine quiescence during pregnancy, while estrogen induces uterine contraction at labor (49 -51). These hormones fluctuate relative to each other throughout life from puberty, through the fertile years, to the postfertile years and also within these life stages during specific physiological states such as estrous, pregnancy, labor, and menopause. Furthermore, both hormones have profound effects on pathophysiological conditions such as leiomyoma, endometriosis, and endometrial cancer.In maternal physiology these hormones induce changes that prepare the mother for pregnancy and aid in conceptus development (11). In most species, a sharp decline in circulating P4 and an increase in estrogen are observed toward parturition (11,38). However, in humans, no marked difference in the levels of circulating P4 or estrogen is noted before or at term (51). Hence, in humans, withdrawal of P4 and responsiveness of the myometrium to circulating estrogen during labor is believed to occur at a functional level, with changes in ho...

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Differential Binding of an SRF/NK-2/MEF2 Transcription Factor Complex in Normal Versus Neoplastic Smooth Muscle Tissues

Cited by 34 publications

References 74 publications

Transcriptional profiling of the megabladder mouse: A unique model of bladder dysmorphogenesis

Transcriptional profiling of the megabladder mouse: A unique model of bladder dysmorphogenesis

Role of serum response factor in the pathogenesis of disease

Effects of combined progesterone and 17β-estradiol treatment on the transcriptome of cultured human myometrial smooth muscle cells

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