scholarly journals Myocardial transcription factors are modulated during pathologic cardiac hypertrophy in vivo

2006 ◽  
Vol 132 (6) ◽  
pp. 1262-1271.e4 ◽  
Author(s):  
Anthony Azakie ◽  
Jeffrey R. Fineman ◽  
Youping He
Keyword(s):  
Transcription Factors ◽  
Cardiac Hypertrophy ◽  
Pathologic Cardiac Hypertrophy

Abstract 104: Protein Kinase GIα Functions in the Cardiac Myocyte as a Tonic Inhibitor of Pathologic Cardiac Hypertrophy In Vivo

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Robert M Blanton ◽  
James P Mendoza ◽  
Mark Aronovitz ◽  
David A Kass ◽  
Michael E Mendelsohn ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Cardiac Hypertrophy ◽  
Cardiac Myocyte ◽  
Heart Weight ◽  
Cross Sectional ◽  
Lv Remodeling ◽  
Exon 1 ◽  
Tibia Length ◽  
Pathologic Cardiac Hypertrophy

Objectives: We and others previously demonstrated that activation of the NO-cGMP-Protein Kinase G (PKG) pathway inhibits cardiac hypertrophy and remodeling in vivo. However, it remains untested whether PKG specifically in the cardiac myocyte (CM) mediates these effects. We therefore tested the hypothesis that PKGIα inhibits pathologic cardiac hypertrophy through a specific role in the CM. Methods and Results: We created and characterized mice with CM-restricted excision of PKGIα. Mice were generated in which the PKGI exon 1 (specific for the Iα isoform) was flanked by loxP sites. We crossed these PKGIα fl/fl mice with αMHC-Cre mice which constitutively express Cre recombinase selectively in the CM. The resultant PKGIα fl/fl / αMHC-Cre+/- mice were compared with PKGIα fl/fl / αMHC-Cre-/- littermate controls (termed PKG CMKO and Ctrl, respectively). By age 3 months (n=5 per genotype), male PKG CMKO mice developed atrial and LV hypertrophy compared with Ctrl littermates PKG CMKO atrial weight/tibia length 0.33 ± 0.03 mg/mm vs 0.22 ± .01 in Ctrl, P <0.05; PKG CMKO LV/TL 5.0 ± 0.2 mg/mm vs 4.1 ± 0.4 in Ctrl, P <0.05). LV CM cross sectional area also increased in the 3 month old PKG CMKO mice (9445 ± 282 pixels PKG CMKO vs 8273 ± 213 in Ctrl, n>400 cells/genotype, 5 hearts per genotype; P <0.001). The systolic index end systolic elastance was decreased in 3 month old PKG CMKO mice (PKG CMKO 3.1 ± 0.4 mmHg/μ l vs 6.1 ± 1.0 in Ctrl-; P <0.05). Importantly, blood pressure did not differ between genotypes. By age 6 months, PKG CMKO mice developed early mortality (3 of 4 PKG CMKO males died at 6 months of age vs 0 of 4 Ctrl males). Total heart and atrial weights of male mice (n=3 PKG CMKO , 4 Ctrl) increased in PKG CMKO mice (heart weight/tibia length 10.8 ± 1.7 mg/mm in PKG CMKO vs 7.1 ± 0.6 in Ctrl; P <0.05; atrial weight/tibia length 2.3 ± 1.1 mg/mm in PKG CMKO vs 0.30 ± 0.1 Ctrl, P <0.05). LV fractional shortening percentage, recorded at 6 months age, trended lower in the PKG CMKO mice as well (35 ± 3% PKG CMKO vs 44 ± 4% Ctrl, P 0.09). Conclusions: These data provide the first evidence that PKGIα functions in the CM as a tonic inhibitor of age-dependent pathologic hypertrophy, supporting further study of PKGIα as a therapeutic target in the prevention and treatment of LV remodeling and congestive heart failure.

Abstract 121: GRK5-NT Regulates the Activity of Calcium-Calmodulin-Dependent Transcription Factors

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Daniela Sorriento ◽  
Anna Fusco ◽  
Gaetano Santulli ◽  
Bruno Trimarco ◽  
Guido Iaccarino
Keyword(s):  
Transcription Factors ◽  
Cardiac Hypertrophy ◽  
Nuclear Translocation ◽  
Binding Activity ◽  
Activated T Cells ◽  
Calmodulin Binding ◽  
Amino Terminal ◽  
Calcium Calmodulin Dependent ◽  
Dna Binding Activity

We have demonstrated that the amino terminal domain (GRK5-NT), which includes the RH domain and the region of binding to calmodulin, is able to regulate cardiac hypertrophy through inhibition of NFκB. Several studies indicate that mechanical stress and neuro-hormonal activation (Angiotensin, phenylephrine, endothelin) increase the levels of intracellular calcium, therefore activating calcineurin, a serine/threonine phosphatase that dephosphorylates nuclear factor of activated T cells (NFAT). Aim of this study is to evaluate the possibility that GRK5-NT regulates calcium-calmodulin dependent transcription factors. To this aim, we infected cardiomyoblasts in culture with an adenovirus encoding for GRK5-NT (AdGRK5-NT) or treated with a synthetic protein (TAT-RH), which reproduce the only RH domain of GRK5. Hypertrophic responses were induced by chronic stimulation of α 1 adrenergic receptors with phenylephrine (PE 10 -7 M,24h) and the levels of GATA4 and NFAT3 were assessed by western blot. PE induces activation and nuclear translocation of GATA4 and NFAT3 (NFAT:+38±3%;GATA4:+46±3% vs control), the treatment with AdGRK5-NT, but TAT-RH, reduces this effect (NFAT:-68±5%;GATA4:-56±2% vs PE). These data suggest that GRK5-NT using the NT domain regulates the activation of calcium-calmodulin dependent transcription factors through a mechanism of competition for binding to calmodulin. To confirm these data, we evaluated the effect of GRK5-NT in vivo in spontaneously hypertensive and hypertrophic rats (SHR). The overexpression of GRK5-NT in the heart was induced by intracardiac injection of 10 10 pfu/ml of AdGRK5-NT. The treatment inhibits nuclear translocation of NFAT3 and GATA4 (NFAT:-55±1%;GATA4:-34±3% vs PE) and is associated with a reduction in their DNA binding activity, as assessed by EMSA (NFAT:-47±1.5%;GATA4:-33±1% vs EP). In conclusion, our data indicate that GRK5-NT is able to regulate cardiac hypertrophy in two ways: inhibition of NFκB through binding and stabilization of IκB nuclear and inhibition activity of calcium- calmodulin dependent transcription factors, possibly by competing with calmodulin binding.

Subnuclear compartmentalization of sequence-specific transcription factors and regulation of eukaryotic gene expression

2005 ◽  
Vol 83 (4) ◽  
pp. 535-547 ◽  
Author(s):  
Gareth N Corry ◽  
D Alan Underhill
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Transcriptional Activation ◽  
Current Knowledge ◽  
Nuclear Architecture ◽  
Subnuclear Localization ◽  
Modular Structures

To date, the majority of the research regarding eukaryotic transcription factors has focused on characterizing their function primarily through in vitro methods. These studies have revealed that transcription factors are essentially modular structures, containing separate regions that participate in such activities as DNA binding, protein–protein interaction, and transcriptional activation or repression. To fully comprehend the behavior of a given transcription factor, however, these domains must be analyzed in the context of the entire protein, and in certain cases the context of a multiprotein complex. Furthermore, it must be appreciated that transcription factors function in the nucleus, where they must contend with a variety of factors, including the nuclear architecture, chromatin domains, chromosome territories, and cell-cycle-associated processes. Recent examinations of transcription factors in the nucleus have clarified the behavior of these proteins in vivo and have increased our understanding of how gene expression is regulated in eukaryotes. Here, we review the current knowledge regarding sequence-specific transcription factor compartmentalization within the nucleus and discuss its impact on the regulation of such processes as activation or repression of gene expression and interaction with coregulatory factors.Key words: transcription, subnuclear localization, chromatin, gene expression, nuclear architecture.

scholarly journals Regulation of sarcomagenesis by the empty spiracles homeobox genes EMX1 and EMX2

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Manuel Pedro Jimenez-García ◽  
Antonio Lucena-Cacace ◽  
Daniel Otero-Albiol ◽  
Amancio Carnero
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Transcription Factors ◽  
Neural Crest ◽  
Tumor Suppressors ◽  
Homeobox Genes ◽  
Neuronal Cell ◽  
Cell Gene Expression

AbstractThe EMX (Empty Spiracles Homeobox) genes EMX1 and EMX2 are two homeodomain gene members of the EMX family of transcription factors involved in the regulation of various biological processes, such as cell proliferation, migration, and differentiation, during brain development and neural crest migration. They play a role in the specification of positional identity, the proliferation of neural stem cells, and the differentiation of certain neuronal cell phenotypes. In general, they act as transcription factors in early embryogenesis and neuroembryogenesis from metazoans to higher vertebrates. The EMX1 and EMX2’s potential as tumor suppressor genes has been suggested in some cancers. Our work showed that EMX1/EMX2 act as tumor suppressors in sarcomas by repressing the activity of stem cell regulatory genes (OCT4, SOX2, KLF4, MYC, NANOG, NES, and PROM1). EMX protein downregulation, therefore, induced the malignance and stemness of cells both in vitro and in vivo. In murine knockout (KO) models lacking Emx genes, 3MC-induced sarcomas were more aggressive and infiltrative, had a greater capacity for tumor self-renewal, and had higher stem cell gene expression and nestin expression than those in wild-type models. These results showing that EMX genes acted as stemness regulators were reproduced in different subtypes of sarcoma. Therefore, it is possible that the EMX genes could have a generalized behavior regulating proliferation of neural crest-derived progenitors. Together, these results indicate that the EMX1 and EMX2 genes negatively regulate these tumor-altering populations or cancer stem cells, acting as tumor suppressors in sarcoma.

scholarly journals RAE-1 ligands for the NKG2D receptor are regulated by E2F transcription factors, which control cell cycle entry

2012 ◽  
Vol 209 (13) ◽  
pp. 2409-2422 ◽  
Author(s):  
Heiyoun Jung ◽  
Benjamin Hsiung ◽  
Kathleen Pestal ◽  
Emily Procyk ◽  
David H. Raulet
Keyword(s):  
Cell Cycle ◽  
Transcription Factors ◽  
Stress Responses ◽  
Transcriptional Activation ◽  
Posttranscriptional Regulation ◽  
Cellular Proliferation ◽  
Control Cell ◽  
T Cell Subsets ◽  
Cell Cycle Entry

The NKG2D stimulatory receptor expressed by natural killer cells and T cell subsets recognizes cell surface ligands that are induced on transformed and infected cells and facilitate immune rejection of tumor cells. We demonstrate that expression of retinoic acid early inducible gene 1 (RAE-1) family NKG2D ligands in cancer cell lines and proliferating normal cells is coupled directly to cell cycle regulation. Raet1 genes are directly transcriptionally activated by E2F family transcription factors, which play a central role in regulating cell cycle entry. Induction of RAE-1 occurred in primary cell cultures, embryonic brain cells in vivo, and cells in healing skin wounds and, accordingly, wound healing was delayed in mice lacking NKG2D. Transcriptional activation by E2Fs is likely coordinated with posttranscriptional regulation by other stress responses. These findings suggest that cellular proliferation, as occurs in cancer cells but also other pathological conditions, is a key signal tied to immune reactions mediated by NKG2D-bearing lymphocytes.

Anti-glioma Efficacy and Mechanism of Action of Tripolinolate A from Tripolium pannonicum

Planta Medica ◽  
2018 ◽  
Vol 84 (11) ◽  
pp. 786-794
Author(s):  
Weiyun Chai ◽  
Lu Chen ◽  
Xiao-Yuan Lian ◽  
Zhizhen Zhang
Keyword(s):  
Cell Cycle ◽  
Transcription Factors ◽  
Glioma Cells ◽  
Inhibitory Effect ◽  
Cell Cycle Regulators ◽  
Expression Levels ◽  
Multiple Tumor ◽  
Glioma Growth

AbstractTripolinolate A as a new bioactive phenolic ester was previously isolated from a halophyte of Tripolium pannonicum. However, the in vitro and in vivo anti-glioma effects and mechanism of tripolinolate A have not been investigated. This study has demonstrated that (1) tripolinolate A inhibited the proliferation of different glioma cells with IC50 values of 7.97 to 14.02 µM and had a significant inhibitory effect on the glioma growth in U87MG xenograft nude mice, (2) tripolinolate A induced apoptosis in glioma cells by downregulating the expressions of antiapoptotic proteins and arrested glioma cell cycle at the G2/M phase by reducing the expression levels of cell cycle regulators, and (3) tripolinolate A also remarkably reduced the expression levels of several glioma metabolic enzymes and transcription factors. All data together suggested that tripolinolate A had significant in vitro and in vivo anti-glioma effects and the regulation of multiple tumor-related regulators and transcription factors might be responsible for the activities of tripolinolate A against glioma.

scholarly journals Targeting of p38 Mitogen-Activated Protein Kinases to MEF2 Transcription Factors

1999 ◽  
Vol 19 (6) ◽  
pp. 4028-4038 ◽  
Author(s):  
Shen-Hsi Yang ◽  
Alex Galanis ◽  
Andrew D. Sharrocks
Keyword(s):  
Transcription Factors ◽  
Transcriptional Activation ◽  
Cellular Response ◽  
Map Kinases ◽  
Biological Response ◽  
Extracellular Signals ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

ABSTRACT Mitogen-activated protein (MAP) kinase-mediated signalling to the nucleus is an important event in the conversion of extracellular signals into a cellular response. However, the existence of multiple MAP kinases which phosphorylate similar phosphoacceptor motifs poses a problem in maintaining substrate specificity and hence the correct biological response. Both the extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK) subfamilies of MAP kinases use a second specificity determinant and require docking to their transcription factor substrates to achieve maximal substrate activation. In this study, we demonstrate that among the different MAP kinases, the MADS-box transcription factors MEF2A and MEF2C are preferentially phosphorylated and activated by the p38 subfamily members p38α and p38β2. The efficiency of phosphorylation in vitro and transcriptional activation in vivo of MEF2A and MEF2C by these p38 subtypes requires the presence of a kinase docking domain (D-domain). Furthermore, the D-domain from MEF2A is sufficient to confer p38 responsiveness on different transcription factors, and reciprocal effects are observed upon the introduction of alternative D-domains into MEF2A. These results therefore contribute to our understanding of signalling to MEF2 transcription factors and demonstrate that the requirement for substrate binding by MAP kinases is an important facet of three different subclasses of MAP kinases (ERK, JNK, and p38).

scholarly journals Activating Signal Cointegrator 2 Belongs to a Novel Steady-State Complex That Contains a Subset of Trithorax Group Proteins

2003 ◽  
Vol 23 (1) ◽  
pp. 140-149 ◽  
Author(s):  
Young-Hwa Goo ◽  
Young Chang Sohn ◽  
Dae-Hwan Kim ◽  
Seung-Whan Kim ◽  
Min-Jung Kang ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Steady State ◽  
Nuclear Receptors ◽  
Transcriptional Activation ◽  
Retinoic Acid Receptor ◽  
Dependent Manner ◽  
Trithorax Group ◽  
Trithorax Group Proteins

ABSTRACT Many transcription coactivators interact with nuclear receptors in a ligand- and C-terminal transactivation function (AF2)-dependent manner. These include activating signal cointegrator 2 (ASC-2), a recently isolated transcriptional coactivator molecule, which is amplified in human cancers and stimulates transactivation by nuclear receptors and numerous other transcription factors. In this report, we show that ASC-2 belongs to a steady-state complex of approximately 2 MDa (ASC-2 complex [ASCOM]) in HeLa nuclei. ASCOM contains retinoblastoma-binding protein RBQ-3, α/β-tubulins, and trithorax group proteins ALR-1, ALR-2, HALR, and ASH2. In particular, ALR-1/2 and HALR contain a highly conserved 130- to 140-amino-acid motif termed the SET domain, which was recently implicated in histone H3 lysine-specific methylation activities. Indeed, recombinant ALR-1, HALR, and immunopurified ASCOM exhibit very weak but specific H3-lysine 4 methylation activities in vitro, and transactivation by retinoic acid receptor appears to involve ligand-dependent recruitment of ASCOM and subsequent transient H3-lysine 4 methylation of the promoter region in vivo. Thus, ASCOM may represent a distinct coactivator complex of nuclear receptors. Further characterization of ASCOM will lead to a better understanding of how nuclear receptors and other transcription factors mediate transcriptional activation.

scholarly journals Distribution of the Transcription Factors Sox9, AP-2, and [Delta]EF1 in Adult Murine Articular and Meniscal Cartilage and Growth Plate

2002 ◽  
Vol 50 (8) ◽  
pp. 1059-1065 ◽  
Author(s):  
Sherri R. Davies ◽  
Shinji Sakano ◽  
Yong Zhu ◽  
Linda J. Sandell
Keyword(s):  
Transcription Factors ◽  
Growth Plate ◽  
Type Ii Collagen ◽  
Nuclear Staining ◽  
Lower Growth ◽  
Biological Studies ◽  
Transcription In Vitro ◽  
Sox9 Protein

The control of extracellular matrix (ECM) production is important for the development, maintenance, and repair of cartilage tissues. Matrix molecule synthesis is generally regulated by the rate of gene transcription determined by DNA transcription factors. We have shown that transcription factors Sox9, AP-2, and [delta]EF1 are able to alter the rate of CD-RAP transcription in vitro: Sox9 upregulates, AP-2 exhibits biphasic effects, and [delta]EF1 represses expression of the CD-RAP gene. To correlate these in vitro activities in vivo, transcription factors were co-immunolocalized with ECM proteins in three different cartilage tissues in which the rates of biosynthesis are quite different: articular, meniscal, and growth plate. Immunoreactivities of type II collagen and CD-RAP were higher in growth plate than in either the articular or meniscal cartilages and correlated positively with Sox9 protein. Sox9 staining decreased with hypertrophy and was low in articular and meniscal cartilages. In contrast, AP-2 and [delta]EF1 were low in proliferating chondrocytes but high in lower growth plate, articular, and meniscal cartilages. This increase was also accompanied by intense nuclear staining. These immunohistochemical results are the first to localize both [delta]EF1 and AP-2 to adult articular, meniscal, and growth plate cartilages and provide in vivo correlation of previous molecular biological studies.

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