Publications by authors named "Christopher L Antos"

20 Publications

  • Page 1 of 1

CTPS forms the cytoophidium in zebrafish.

Exp Cell Res 2021 Jun 12;405(2):112684. Epub 2021 Jun 12.

School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China; Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, OX1 3PT, United Kingdom. Electronic address:

Cytidine triphosphate synthase (CTPS) catalyzes the rate-limiting step of de novo CTP biosynthesis. An intracellular structure of CTPS, the cytoophidium, has been found in many organisms including prokaryotes and eukaryotes. Formation of the cytoophidium has been suggested to regulate the activity and stability of CTPS and may participate in certain physiological events. Herein, we demonstrate that both CTPS1a and CTPS1b in zebrafish are able to form the cytoophidium in cultured cells. A point mutation, H355A, abrogates cytoophidium assembly of zebrafish CTPS1a and CTPS1b. In addition, we show the presence of CTPS cytoophidia in multiple tissues of larval and adult fish under normal conditions, while treatment with a CTPS inhibitor 6-diazo-5-oxo-l-norleucine (DON) can induce more cytoophidia in some tissues. Our findings reveal that forming the CTPS cytoophidium is a natural phenomenon of zebrafish and provide valuable information for future research on the physiological importance of this intracellular structure in vertebrates.
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http://dx.doi.org/10.1016/j.yexcr.2021.112684DOI Listing
June 2021

IMPDH forms the cytoophidium in zebrafish.

Dev Biol 2021 May 25;478:89-101. Epub 2021 May 25.

School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China. Electronic address:

Inosine monophosphate dehydrogenase (IMPDH) catalyzes the rate-limiting step in de novo guanine nucleotide biosynthesis. Its activity is negatively regulated by the binding of GTP. IMPDH can form a membraneless subcellular structure termed the cytoophidium in response to certain changes in the metabolic status of the cell. The polymeric form of IMPDH, which is the subunit of the cytoophidium, has been shown to be more resistant to the inhibition by GTP at physiological concentrations, implying a functional correlation between cytoophidium formation and the upregulation of GTP biosynthesis. Herein we demonstrate that zebrafish IMPDH1b and IMPDH2 isoforms can assemble abundant cytoophidium in most of cultured cells under stimuli, while zebrafish IMPDH1a shows distinctive properties of forming the cytoophidium in different cell types. Point mutations that disrupt cytoophidium structure in mammalian models also prevent the aggregation of zebrafish IMPDHs. In addition, we discover the presence of the IMPDH cytoophidium in various tissues of larval and adult fish under normal growth conditions. Our results reveal that polymerization and cytoophidium assembly of IMPDH can be a regulatory machinery conserved among vertebrates, and with specific physiological purposes.
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http://dx.doi.org/10.1016/j.ydbio.2021.05.017DOI Listing
May 2021

A calcineurin-mediated scaling mechanism that controls a K-leak channel to regulate morphogen and growth factor transcription.

Elife 2021 Apr 8;10. Epub 2021 Apr 8.

School of Life Sciences and Technology, ShanghaiTech University, Shanghai, China.

The increase in activity of the two-pore potassium-leak channel Kcnk5b maintains allometric juvenile growth of adult zebrafish appendages. However, it remains unknown how this channel maintains allometric growth and how its bioelectric activity is regulated to scale these anatomical structures. We show the activation of Kcnk5b is sufficient to activate several genes that are part of important development programs. We provide in vivo transplantation evidence that the activation of gene transcription is cell autonomous. We also show that Kcnk5b will induce the expression of different subsets of the tested developmental genes in different cultured mammalian cell lines, which may explain how one electrophysiological stimulus can coordinately regulate the allometric growth of diverse populations of cells in the fin that use different developmental signals. We also provide evidence that the post-translational modification of serine 345 in Kcnk5b by calcineurin regulates channel activity to scale the fin. Thus, we show how an endogenous bioelectric mechanism can be regulated to promote coordinated developmental signaling to generate and scale a vertebrate appendage.
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http://dx.doi.org/10.7554/eLife.60691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110307PMC
April 2021

3D Culture Method for Alzheimer's Disease Modeling Reveals Interleukin-4 Rescues Aβ42-Induced Loss of Human Neural Stem Cell Plasticity.

Dev Cell 2018 07;46(1):85-101.e8

German Center for Neurodegenerative Diseases (DZNE) Dresden, Helmholtz Association, Arnoldstr. 18, 01307 Dresden, Germany; Center for Regenerative Therapies (CRTD), Technische Universität Dresden, Fetscherstr. 105, 01307 Dresden, Germany. Electronic address:

Neural stem cells (NSCs) constitute an endogenous reservoir for neurons that could potentially be harnessed for regenerative therapies in disease contexts such as neurodegeneration. However, in Alzheimer's disease (AD), NSCs lose plasticity and thus possible regenerative capacity. We investigate how NSCs lose their plasticity in AD by using starPEG-heparin-based hydrogels to establish a reductionist 3D cell-instructive neuro-microenvironment that promotes the proliferative and neurogenic ability of primary and induced human NSCs. We find that administration of AD-associated Amyloid-β42 causes classical neuropathology and hampers NSC plasticity by inducing kynurenic acid (KYNA) production. Interleukin-4 restores NSC proliferative and neurogenic ability by suppressing the KYNA-producing enzyme Kynurenine aminotransferase (KAT2), which is upregulated in APP/PS1dE9 mouse model of AD and in postmortem human AD brains. Thus, our culture system enables a reductionist investigation of regulation of human NSC plasticity for the identification of potential therapeutic targets for intervention in AD.
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http://dx.doi.org/10.1016/j.devcel.2018.06.005DOI Listing
July 2018

Human TAU overexpression results in TAU hyperphosphorylation without neurofibrillary tangles in adult zebrafish brain.

Sci Rep 2017 10 11;7(1):12959. Epub 2017 Oct 11.

German Center for Neurodegenerative Diseases (DZNE), Arnoldstrasse 18, 01307, Dresden, Germany.

Microtubule-associated TAU protein is a pathological hallmark in Alzheimer's disease (AD), where hyperphosphorylation of TAU generates neurofibrillary tangles. To investigate the effects of TAU in a regenerative adult vertebrate brain system, we generated a cre/lox-based transgenic model of zebrafish that chronically expresses human TAU, which is a variant of human TAU protein that forms neurofibrillary tangles in mouse models and humans. Interestingly, we found that although chronic and abundant expression of TAU starting from early embryonic development led to hyperphosphorylation, TAU did not form oligomers and neurofibrillary tangles, and did not cause elevated apoptosis and microglial activation, which are classical symptoms of tauopathies in mammals. Additionally, TAU neither increased neural stem cell proliferation nor activated the expression of regenerative factor Interleukin-4, indicating that TAU toxicity is prevented in the adult zebrafish brain. By combining TAU expression with our established Aβ42 toxicity model, we found that Aβ42 ceases to initiate neurofibrillary tangle formation by TAU, and TAU does not exacerbate the toxicity of Aβ42. Therefore, our results propose a cellular mechanism that protects the adult zebrafish brain against tauopathies, and our model can be used to understand how TAU toxicity can be prevented in humans.
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http://dx.doi.org/10.1038/s41598-017-13311-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5636889PMC
October 2017

Chronic loss of inhibitor-1 diminishes cardiac RyR2 phosphorylation despite exaggerated CaMKII activity.

Naunyn Schmiedebergs Arch Pharmacol 2017 Aug 27;390(8):857-862. Epub 2017 Apr 27.

Department of Pharmacology and Toxicology, Carl Gustav Carus Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.

Inhibitor-1 (I-1) modulates protein phosphatase 1 (PP1) activity and thereby counteracts the phosphorylation by kinases. I-1 is downregulated and deactivated in failing hearts, but whether its role is beneficial or detrimental remains controversial, and opposing therapeutic strategies have been proposed. Overactivity of Ca/calmodulin-dependent protein kinase II (CaMKII) with hyperphosphorylation of ryanodine receptors (RyR2) at the CaMKII-site is recognized to be central for heart failure and arrhythmias. Using an I-1-deficient mouse line as well as transfected cell lines, we investigated the effects of acute and chronic modulation of I-1 on CaMKII activity and RyR2 phosphorylation. We demonstrate that I-1 acutely modulates CaMKII by regulating PP1 activity. However, while ablation of I-1 should thus limit CaMKII-activation, we unexpectedly found exaggerated CaMKII-activation under β-adrenergic stress upon chronic loss of I-1 in knockout mice. We unraveled that this is due to chronic upregulation of the exchange protein activated by cAMP (EPAC) leading to augmented CaMKII activation, and using computational modeling validated that an increase in EPAC expression can indeed explain our experimental findings. Interestingly, at the level of RyR2, the increase in PP1 activity more than outweighed the increase in CaMKII activity, resulting in reduced RyR phosphorylation at Ser-2814. Exaggerated CaMKII activation due to counterregulatory mechanisms upon loss of I-1 is an important caveat with respect to suggested therapeutic I-1-inhibition, as CaMKII overactivity has been heavily implicated in several cardiac pathologies.
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http://dx.doi.org/10.1007/s00210-017-1376-1DOI Listing
August 2017

Making human cardiomyocytes up to date: Derivation, maturation state and perspectives.

Int J Cardiol 2017 Aug 24;241:379-386. Epub 2017 Mar 24.

Institute of Pharmacology and Toxicology, Technische Universität Dresden, Fetscherstr. 74, 01307 Dresden, Germany. Electronic address:

In vitro generation of cardiomyocytes (CMs) from human cells opens the possibility to develop patient-specific therapies to various cardiomyopathies. By establishing the in vitro reprograming methods that produce human CMs, we learn about what is involved in the development of specific CM subtypes. In this review, we summarize the latest achievements in CM generation technologies, emphasizing the differentiation methods of specific CM subtypes. We also relate the biological properties and functions of the in vitro-generated CMs to those of their in vivo counterparts. Furthermore, we describe the main problem of current CM derivation methods - maturation of CMs. We subsequently discuss biochemical and physical stimuli that are used to overcome the maturation problems of in vitro-derived CMs. As a result, a more holistic approach with controllable environment and timing of specific stimuli for creation of more mature engineered heart tissues is described as well. Finally, we propose a novel approach in which enhancing energy transfer mechanisms in the immature CMs might help to overcome the current hurdle of incomplete in vitro differentiation.
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http://dx.doi.org/10.1016/j.ijcard.2017.03.099DOI Listing
August 2017

Simplet/Fam53b is required for Wnt signal transduction by regulating β-catenin nuclear localization.

Development 2014 Sep;141(18):3529-39

DFG-Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, Fetscherstrasse 105, Dresden 01307, Germany

Canonical β-catenin-dependent Wnt signal transduction is important for several biological phenomena, such as cell fate determination, cell proliferation, stem cell maintenance and anterior-posterior axis formation. The hallmark of canonical Wnt signaling is the translocation of β-catenin into the nucleus where it activates gene transcription. However, the mechanisms regulating β-catenin nuclear localization are poorly understood. We show that Simplet/Fam53B (Smp) is required for Wnt signaling by positively regulating β-catenin nuclear localization. In the zebrafish embryo, the loss of smp blocks the activity of two β-catenin-dependent reporters and the expression of Wnt target genes, and prevents nuclear accumulation of β-catenin. Conversely, overexpression of smp increases β-catenin nuclear localization and transcriptional activity in vitro and in vivo. Expression of mutant Smp proteins lacking either the nuclear localization signal or the β-catenin interaction domain reveal that the translocation of Smp into the nucleus is essential for β-catenin nuclear localization and Wnt signaling in vivo. We also provide evidence that mammalian Smp is involved in regulating β-catenin nuclear localization: the protein colocalizes with β-catenin-dependent gene expression in mouse intestinal crypts; siRNA knockdown of Smp reduces β-catenin nuclear localization and transcriptional activity; human SMP mediates β-catenin transcriptional activity in a dose-dependent manner; and the human SMP protein interacts with human β-catenin primarily in the nucleus. Thus, our findings identify the evolutionary conserved SMP protein as a regulator of β-catenin-dependent Wnt signal transduction.
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http://dx.doi.org/10.1242/dev.108415DOI Listing
September 2014

Reverse genetic morpholino approach using cardiac ventricular injection to transfect multiple difficult-to-target tissues in the zebrafish larva.

J Vis Exp 2014 Jun 17(88). Epub 2014 Jun 17.

DFG-Center for Regenerative Therapies Dresden, Technische Universität Dresden;

The zebrafish is an important model to understand the cell and molecular biology of organ and appendage regeneration. However, molecular strategies to employ reverse genetics have not yet been adequately developed to assess gene function in regeneration or tissue homeostasis during larval stages after zebrafish embryogenesis, and several tissues within the zebrafish larva are difficult to target. Intraventricular injections of gene-specific morpholinos offer an alternative method for the current inability to genomically target zebrafish genes in a temporally controlled manner at these stages. This method allows for complete dispersion and subsequent incorporation of the morpholino into various tissues throughout the body, including structures that were formerly impossible to reach such as those in the larval caudal fin, a structure often used to noninvasively research tissue regeneration. Several genes activated during larval finfold regeneration are also present in regenerating adult vertebrate tissues, so the larva is a useful model to understand regeneration in adults. This morpholino dispersion method allows for the quick and easy identification of genes required for the regeneration of larval tissues as well as other physiological phenomena regulating tissue homeostasis after embryogenesis. Therefore, this delivery method provides a currently needed strategy for temporal control to the evaluation of gene function after embryogenesis. 
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http://dx.doi.org/10.3791/51595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4195391PMC
June 2014

Calcineurin regulates coordinated outgrowth of zebrafish regenerating fins.

Dev Cell 2014 Mar 20;28(5):573-87. Epub 2014 Feb 20.

DFG-Center for Regenerative Therapies Dresden, Technische Universität Dresden, Fetscherstrasse 105, 01307 Dresden, Germany. Electronic address:

Vertebrates develop organs and appendages in a proportionally coordinated manner, and animals that regenerate them do so to the same dimensions as the original structures. Coordinated proportional growth involves controlled regulation between allometric and isometric growth programs, but it is unclear what executes this control. We show that calcineurin inhibition results in continued allometric outgrowth of regenerating fins beyond their original dimensions. Calcineurin inhibition also maintains allometric growth of juvenile fins and induces it in adult fins. Furthermore, calcineurin activity is low when the regeneration rate is highest, and its activity increases as the rate decreases. Growth measurements and morphometric analysis of proximodistal asymmetry indicate that calcineurin inhibition shifts fin regeneration from a distal growth program to a proximal program. This shift is associated with the promotion of retinoic acid signaling. Thus, we identified a calcineurin-mediated mechanism that operates as a molecular switch between position-associated isometric and allometric growth programs.
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http://dx.doi.org/10.1016/j.devcel.2014.01.019DOI Listing
March 2014

Vertebrates that regenerate as models for guiding stem cels.

Adv Exp Med Biol 2010 ;695:184-214

DFG-Center for Regenerative Therapies Dresden, Technische Universität Dresden, Tatzberg 47/49, 01307, Dresden, Germany,

There are several animal model organisms that have the ability to regenerate severe injuries by stimulating local cells to restore damaged and lost organs and appendages. In this chapter, we will describe how various vertebrate animals regenerate different structures (central nervous system, heart and appendages) as well as detail specific cellular and molecular features concerning the regeneration of these structures.
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http://dx.doi.org/10.1007/978-1-4419-7037-4_13DOI Listing
April 2016

Simplet controls cell proliferation and gene transcription during zebrafish caudal fin regeneration.

Dev Biol 2009 Jan 17;325(2):329-40. Epub 2008 Oct 17.

Max-Planck Institut für Entwicklungsbiologie, Abteilung Genetik, Spemannstrasse 35, 72076 Tübingen, Germany.

Two hallmarks of vertebrate epimorphic regeneration are a significant increase in the proliferation of normally quiescent cells and a re-activation of genes that are active during embryonic development. It is unclear what the molecular determinants are that regulate these events and how they are coordinated. Zebrafish have the ability to regenerate several compound structures by regulating cell proliferation and gene transcription. We report that fam53b/simplet (smp) regulates both cell proliferation and the transcription of specific genes. In situ hybridization and quantitative RT-PCR experiments showed that amputation of zebrafish hearts and fins resulted in strong up-regulation of the smp gene. In regenerating adult fin, smp expression remained strong in the distal mesenchyme which later expanded to the basal layers of the distal epidermis and distal tip epithelium. Morpholino knockdown of smp reduced regenerative outgrowth by decreasing cell proliferation as measured by BrdU incorporation and histone H3 phosphorylation. In addition, smp knockdown increased the expression of msxb, msxc, and shh, as well as the later formation of ectopic bone. Taken together, these data indicate a requirement for smp in fin regeneration through control of cell proliferation, the regulation of specific genes and proper bone patterning.
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http://dx.doi.org/10.1016/j.ydbio.2008.09.032DOI Listing
January 2009

Blocking cardiac growth in hypertrophic cardiomyopathy induces cardiac dysfunction and decreased survival only in males.

Am J Physiol Heart Circ Physiol 2007 Feb 29;292(2):H838-45. Epub 2006 Sep 29.

Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, Campus Box 347, Boulder, Colorado 80309-0347, USA.

Mutations in myosin heavy chain (MyHC) can cause hypertrophic cardiomyopathy (HCM) that is characterized by hypertrophy, histopathology, contractile dysfunction, and sudden death. The signaling pathways involved in the pathology of HCM have not been elucidated, and an unresolved question is whether blocking hypertrophic growth in HCM may be maladaptive or beneficial. To address these questions, a mouse model of HCM was crossed with an antihypertrophic mouse model of constitutive activated glycogen synthase kinase-3beta (caGSK-3beta). Active GSK-3beta blocked cardiac hypertrophy in both male and female HCM mice. However, doubly transgenic males (HCM/GSK-3beta) demonstrated depressed contractile function, reduced sarcoplasmic (endo) reticulum Ca(2+)-ATPase (SERCA) expression, elevated atrial natriuretic factor (ANF) expression, and premature death. In contrast, female HCM/GSK-3beta double transgenic mice exhibited similar cardiac histology, function, and survival to their female HCM littermates. Remarkably, dietary modification from a soy-based diet to a casein-based diet significantly improved survival in HCM/GSK-3beta males. These findings indicate that activation of GSK-3beta is sufficient to limit cardiac growth in this HCM model and the consequence of caGSK-3beta was sexually dimorphic. Furthermore, these results show that blocking hypertrophy by active GSK-3beta in this HCM model is not therapeutic.
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http://dx.doi.org/10.1152/ajpheart.00615.2006DOI Listing
February 2007

Myocardin induces cardiomyocyte hypertrophy.

Circ Res 2006 Apr 23;98(8):1089-97. Epub 2006 Mar 23.

Carolina Cardiovascular Biology Center, Department of Cell and Developmental Biology, University of North Carolina, Chapel Hill, NC 27599-7126, USA.

In response to stress signals, postnatal cardiomyocytes undergo hypertrophic growth accompanied by activation of a fetal gene program, assembly of sarcomeres, and cellular enlargement. We show that hypertrophic signals stimulate the expression and transcriptional activity of myocardin, a cardiac and smooth muscle-specific coactivator of serum response factor (SRF). Consistent with a role for myocardin as a transducer of hypertrophic signals, forced expression of myocardin in cardiomyocytes is sufficient to substitute for hypertrophic signals and induce cardiomyocyte hypertrophy and the fetal cardiac gene program. Conversely, a dominant-negative mutant form of myocardin, which retains the ability to associate with SRF but is defective in transcriptional activation, blocks cardiomyocyte hypertrophy induced by hypertrophic agonists such as phenylephrine and leukemia inhibitory factor. Myocardin-dependent hypertrophy can also be partially repressed by histone deacetylase 5, a transcriptional repressor of myocardin. These findings identify myocardin as a nuclear effector of hypertrophic signaling pathways that couples stress signals to a transcriptional program for postnatal cardiac growth and remodeling.
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http://dx.doi.org/10.1161/01.RES.0000218781.23144.3eDOI Listing
April 2006

Glycogen synthase kinase-3beta mediates convergence of protection signaling to inhibit the mitochondrial permeability transition pore.

J Clin Invest 2004 Jun;113(11):1535-49

Laboratory of Cardiovascular Science, Gerontology Research Center, Intramural Research Program, National Institute on Aging, NIH, Baltimore, Maryland 21224-6825, USA.

Environmental stresses converge on the mitochondria that can trigger or inhibit cell death. Excitable, postmitotic cells, in response to sublethal noxious stress, engage mechanisms that afford protection from subsequent insults. We show that reoxygenation after prolonged hypoxia reduces the reactive oxygen species (ROS) threshold for the mitochondrial permeability transition (MPT) in cardiomyocytes and that cell survival is steeply negatively correlated with the fraction of depolarized mitochondria. Cell protection that exhibits a memory (preconditioning) results from triggered mitochondrial swelling that causes enhanced substrate oxidation and ROS production, leading to redox activation of PKC, which inhibits glycogen synthase kinase-3beta (GSK-3beta). Alternatively, receptor tyrosine kinase or certain G protein-coupled receptor activation elicits cell protection (without mitochondrial swelling or durable memory) by inhibiting GSK-3beta, via protein kinase B/Akt and mTOR/p70(s6k) pathways, PKC pathways, or protein kinase A pathways. The convergence of these pathways via inhibition of GSK-3beta on the end effector, the permeability transition pore complex, to limit MPT induction is the general mechanism of cardiomyocyte protection.
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http://dx.doi.org/10.1172/JCI19906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC419483PMC
June 2004

Loss of NFAT5 results in renal atrophy and lack of tonicity-responsive gene expression.

Proc Natl Acad Sci U S A 2004 Feb;101(8):2392-7

Department of Pathology, Harvard Medical School and Center for Blood Research, Institute for Biomedical Research, 200 Longwood Avenue, Boston MA 02115, USA.

The transcription factor NFAT5/TonEBP, a member of the NFAT/Rel family of transcription factors, has been implicated in diverse cellular responses, including the response to osmotic stress, integrin-dependent cell migration, T cell activation, and the Ras pathway in Drosophila. To clarify the in vivo role of NFAT5, we generated NFAT5-null mice. Homozygous mutants were genetically underrepresented after embryonic day 14.5. Surviving mice manifested a progressive and profound atrophy of the kidney medulla with impaired activation of several osmoprotective genes, including those encoding aldose reductase, Na+/Cl--coupled betaine/gamma-aminobutyric acid transporter, and the Na+/myo-inositol cotransporter. The aldose reductase gene is controlled by a tonicity-responsive enhancer, which was refractory to hypertonic stress in fibroblasts lacking NFAT5, establishing this enhancer as a direct transcriptional target of NFAT5. Our findings demonstrate a central role for NFAT5 as a tonicity-responsive transcription factor required for kidney homeostasis and function.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC356961PMC
http://dx.doi.org/10.1073/pnas.0308703100DOI Listing
February 2004

Common genomic response in different mouse models of beta-adrenergic-induced cardiomyopathy.

Circulation 2003 Dec 17;108(23):2926-33. Epub 2003 Nov 17.

University of Medicine and Dentistry of New Jersey and New Jersey Medical School, Newark, NJ 07101, USA.

Background: Although beta-adrenergic receptor (AR) blockade therapy is beneficial in the treatment of heart failure, little is known regarding the transcriptional mechanisms underlying this salutary action.

Methods And Results: In the present study, we screened mice overexpressing Gsalpha, beta1AR, beta2AR, or protein kinase A to test if a common genomic pathway exists in different models with enhanced beta-adrenergic signaling. In mice overexpressing Gsalpha, differentially expressed genes were identified by mRNA profiling. In addition to well-known markers of cardiac hypertrophy (atrial natriuretic factor, CARP, and beta-myosin heavy chain), uncoupling protein 2 (UCP2), a protein involved in the control of mitochondrial membrane potential, and four-and-a-half LIM domain protein-1 (FHL1), a member of the LIM protein family, were predicted to be upregulated. Upregulation of these genes was confirmed by quantitative reverse transcriptase-polymerase chain reaction at all time points tested during the development of cardiomyopathy in mice overexpressing Gsalpha. In mice overexpressing beta1AR, beta2AR, or protein kinase A, increased UCP2 and FHL1 expression was also observed at the onset of cardiomyopathy. BetaAR blockade treatment reversed the cardiomyopathy and suppressed the increased expression of UCP2 and FHL1 in mice overexpressing Gsalpha.

Conclusions: UCP2 and FHL1 are important candidate genes that correlate with the development of betaAR-induced cardiomyopathy in different mouse models with enhanced betaAR signaling. In addition to preserving cardiac function, betaAR blockade treatment also prevents the genomic regulation that correlates with the onset of heart failure.
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http://dx.doi.org/10.1161/01.CIR.0000101922.18151.7BDOI Listing
December 2003

Dose-dependent blockade to cardiomyocyte hypertrophy by histone deacetylase inhibitors.

J Biol Chem 2003 Aug 20;278(31):28930-7. Epub 2003 May 20.

Department of Molecular Biology, The University of Texas, Southwestern Medical Center at Dallas, Dallas, Texas 75390-9148, USA.

Postnatal cardiac myocytes respond to stress signals by hypertrophic growth and activation of a fetal gene program. Recently, we showed that class II histone deacetylases (HDACs) suppress cardiac hypertrophy, and mice lacking the class II HDAC, HDAC9, are sensitized to hypertrophic signals. To further define the roles of HDACs in cardiac hypertrophy, we analyzed the effects of HDAC inhibitors on the responsiveness of primary cardiomyocytes to hypertrophic agonists. Paradoxically, HDAC inhibitors imposed a dose-dependent blockade to hypertrophy and fetal gene activation. We conclude that distinct HDACs play positive or negative roles in the control of cardiomyocyte hypertrophy. HDAC inhibitors are currently being tested in clinical trials as anti-cancer agents. Our results suggest that these inhibitors may also hold promising clinical value as therapeutics for cardiac hypertrophy and heart failure.
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http://dx.doi.org/10.1074/jbc.M303113200DOI Listing
August 2003

Class II histone deacetylases act as signal-responsive repressors of cardiac hypertrophy.

Cell 2002 Aug;110(4):479-88

Department of Molecular Biology, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas 75390, USA.

The heart responds to stress signals by hypertrophic growth, which is accompanied by activation of the MEF2 transcription factor and reprogramming of cardiac gene expression. We show here that class II histone deacetylases (HDACs), which repress MEF2 activity, are substrates for a stress-responsive kinase specific for conserved serines that regulate MEF2-HDAC interactions. Signal-resistant HDAC mutants lacking these phosphorylation sites are refractory to hypertrophic signaling and inhibit cardiomyocyte hypertrophy. Conversely, mutant mice lacking the class II HDAC, HDAC9, are sensitized to hypertrophic signals and exhibit stress-dependent cardiomegaly. Thus, class II HDACs act as signal-responsive suppressors of the transcriptional program governing cardiac hypertrophy and heart failure.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4459650PMC
http://dx.doi.org/10.1016/s0092-8674(02)00861-9DOI Listing
August 2002

Activated glycogen synthase-3 beta suppresses cardiac hypertrophy in vivo.

Proc Natl Acad Sci U S A 2002 Jan 8;99(2):907-12. Epub 2002 Jan 8.

Department of Molecular Biology, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390-9148, USA.

The adult myocardium responds to a variety of pathologic stimuli by hypertrophic growth that frequently progresses to heart failure. The calcium/calmodulin-dependent protein phosphatase calcineurin is a potent transducer of hypertrophic stimuli. Calcineurin dephosphorylates members of the nuclear factor of activated T cell (NFAT) family of transcription factors, which results in their translocation to the nucleus and activation of calcium-dependent genes. Glycogen synthase kinase-3 (GSK-3) phosphorylates NFAT proteins and antagonizes the actions of calcineurin by stimulating NFAT nuclear export. To determine whether activated GSK-3 can act as an antagonist of hypertrophic signaling in the adult heart in vivo, we generated transgenic mice that express a constitutively active form of GSK-3 beta under control of a cardiac-specific promoter. These mice were physiologically normal under nonstressed conditions, but their ability to mount a hypertrophic response to calcineurin activation was severely impaired. Similarly, cardiac-specific expression of activated GSK-3 beta diminished hypertrophy in response to chronic beta-adrenergic stimulation and pressure overload. These findings reveal a role for GSK-3 beta as an inhibitor of hypertrophic signaling in the intact myocardium and suggest that elevation of cardiac GSK-3 beta activity may provide clinical benefit in the treatment of pathologic hypertrophy and heart failure.
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http://dx.doi.org/10.1073/pnas.231619298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC117404PMC
January 2002
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