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Discovering small molecules as Wnt inhibitors that promote heart regeneration and injury repair.
Xie S, Fu W, Yu G, Hu X, Lai KS, Peng X, Zhou Y, Zhu X, Christov P, Sawyer L, Ni TT, Sulikowski GA, Yang Z, Lee E, Zeng C, Wang WE, Zhong TP
(2019) J Mol Cell Biol :
Show Abstract · Added April 10, 2019
There are intense interests in discovering proregenerative medicine leads that can promote cardiac differentiation and regeneration, as well as repair damaged heart tissues. We have combined zebrafish embryo-based screens with cardiomyogenesis assays to discover selective small molecules that modulate heart development and regeneration with minimal adverse effects. Two related compounds with novel structures, named as Cardiomogen1 and 2 (CDMG1 and CDMG2), were identified for their capacity to promote myocardial hyperplasia through expansion of the cardiac progenitor cell population. We find that Cardiomogen acts as a Wnt inhibitor by targeting β-catenin and reducing Tcf/Lef-mediated transcription in cultured cells. CDMG treatment of amputated zebrafish hearts reduces nuclear β-catenin in injured heart tissue, increases cardiomyocyte (CM) proliferation, and expedites wound healing, thus accelerating cardiac muscle regeneration. Importantly, Cardiomogen can alleviate the functional deterioration of mammalian hearts after myocardial infarction. Injured hearts exposed to CDMG1 display increased newly formed CMs and reduced fibrotic scar tissue, which are in part attributable to the β-catenin reduction. Our findings indicate Cardiomogen as a Wnt inhibitor in enhancing injury-induced CM proliferation and heart regeneration, highlighting the values of embryo-based small molecule screens in discovery of effective and safe medicine leads.
© The Author(s) 2019. Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS.
0 Communities
1 Members
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0 MeSH Terms
Transcriptional Maintenance of Pancreatic Acinar Identity, Differentiation, and Homeostasis by PTF1A.
Hoang CQ, Hale MA, Azevedo-Pouly AC, Elsässer HP, Deering TG, Willet SG, Pan FC, Magnuson MA, Wright CV, Swift GH, MacDonald RJ
(2016) Mol Cell Biol 36: 3033-3047
MeSH Terms: Acinar Cells, Animals, Cell Differentiation, Gene Expression Profiling, Gene Expression Regulation, Gene Knockout Techniques, Homeostasis, Mice, Pancreas, Exocrine, Protein Unfolding, Sequence Analysis, RNA, Transcription Factors, Transcription, Genetic, Unfolded Protein Response
Show Abstract · Added November 1, 2016
Maintenance of cell type identity is crucial for health, yet little is known of the regulation that sustains the long-term stability of differentiated phenotypes. To investigate the roles that key transcriptional regulators play in adult differentiated cells, we examined the effects of depletion of the developmental master regulator PTF1A on the specialized phenotype of the adult pancreatic acinar cell in vivo Transcriptome sequencing and chromatin immunoprecipitation sequencing results showed that PTF1A maintains the expression of genes for all cellular processes dedicated to the production of the secretory digestive enzymes, a highly attuned surveillance of unfolded proteins, and a heightened unfolded protein response (UPR). Control by PTF1A is direct on target genes and indirect through a ten-member transcription factor network. Depletion of PTF1A causes an imbalance that overwhelms the UPR, induces cellular injury, and provokes acinar metaplasia. Compromised cellular identity occurs by derepression of characteristic stomach genes, some of which are also associated with pancreatic ductal cells. The loss of acinar cell homeostasis, differentiation, and identity is directly relevant to the pathologies of pancreatitis and pancreatic adenocarcinoma.
Copyright © 2016, American Society for Microbiology. All Rights Reserved.
2 Communities
2 Members
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14 MeSH Terms
Prostaglandin E2 receptor EP3 regulates both adipogenesis and lipolysis in mouse white adipose tissue.
Xu H, Fu JL, Miao YF, Wang CJ, Han QF, Li S, Huang SZ, Du SN, Qiu YX, Yang JC, Gustafsson JÅ, Breyer RM, Zheng F, Wang NP, Zhang XY, Guan YF
(2016) J Mol Cell Biol 8: 518-529
MeSH Terms: Adipocytes, Adipogenesis, Adipose Tissue, White, Animals, Cell Differentiation, Gene Deletion, Inflammation, Insulin Resistance, Lipolysis, Lipoproteins, VLDL, Mice, Mice, Obese, Obesity, Phenotype, Protein Isoforms, Rats, Sprague-Dawley, Receptors, Prostaglandin E, EP3 Subtype, Signal Transduction, Triglycerides
Show Abstract · Added February 7, 2019
Among the four prostaglandin E2 receptors, EP3 receptor is the one most abundantly expressed in white adipose tissue (WAT). The mouse EP3 gene gives rise to three isoforms, namely EP3α, EP3β, and EP3γ, which differ only at their C-terminal tails. To date, functions of EP3 receptor and its isoforms in WAT remain incompletely characterized. In this study, we found that the expression of all EP3 isoforms were downregulated in WAT of both db/db and high-fat diet-induced obese mice. Genetic ablation of three EP3 receptor isoforms (EP3 mice) or EP3α and EP3γ isoforms with EP3β intact (EP3β mice) led to an obese phenotype with increased food intake, decreased motor activity, reduced insulin sensitivity, and elevated serum triglycerides. Since the differentiation of preadipocytes and mouse embryonic fibroblasts to adipocytes was markedly facilitated by either pharmacological blockade or genetic deletion/inhibition of EP3 receptor via the cAMP/PKA/PPARγ pathway, increased adipogenesis may contribute to obesity in EP3 and EP3β mice. Moreover, both EP3 and EP3β mice had increased lipolysis in WAT mainly due to the activated cAMP/PKA/hormone-sensitive lipase pathway. Taken together, our findings suggest that EP3 receptor and its α and γ isoforms are involved in both adipogenesis and lipolysis and influence food intake, serum lipid levels, and insulin sensitivity.
© The Author (2016). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS. All rights reserved.
1 Communities
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MeSH Terms
Endogenous Hot Spots of De Novo Telomere Addition in the Yeast Genome Contain Proximal Enhancers That Bind Cdc13.
Obodo UC, Epum EA, Platts MH, Seloff J, Dahlson NA, Velkovsky SM, Paul SR, Friedman KL
(2016) Mol Cell Biol 36: 1750-63
MeSH Terms: Binding Sites, DNA Breaks, Double-Stranded, DNA Repair, DNA, Fungal, Enhancer Elements, Genetic, Genome, Fungal, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Telomerase, Telomere, Telomere-Binding Proteins
Show Abstract · Added April 8, 2019
DNA double-strand breaks (DSBs) pose a threat to genome stability and are repaired through multiple mechanisms. Rarely, telomerase, the enzyme that maintains telomeres, acts upon a DSB in a mutagenic process termed telomere healing. The probability of telomere addition is increased at specific genomic sequences termed sites of repair-associated telomere addition (SiRTAs). By monitoring repair of an induced DSB, we show that SiRTAs on chromosomes V and IX share a bipartite structure in which a core sequence (Core) is directly targeted by telomerase, while a proximal sequence (Stim) enhances the probability of de novo telomere formation. The Stim and Core sequences are sufficient to confer a high frequency of telomere addition to an ectopic site. Cdc13, a single-stranded DNA binding protein that recruits telomerase to endogenous telomeres, is known to stimulate de novo telomere addition when artificially recruited to an induced DSB. Here we show that the ability of the Stim sequence to enhance de novo telomere addition correlates with its ability to bind Cdc13, indicating that natural sites at which telomere addition occurs at high frequency require binding by Cdc13 to a sequence 20 to 100 bp internal from the site at which telomerase acts to initiate de novo telomere addition.
Copyright © 2016, American Society for Microbiology. All Rights Reserved.
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1 Members
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MeSH Terms
The Endothelial Prolyl-4-Hydroxylase Domain 2/Hypoxia-Inducible Factor 2 Axis Regulates Pulmonary Artery Pressure in Mice.
Kapitsinou PP, Rajendran G, Astleford L, Michael M, Schonfeld MP, Fields T, Shay S, French JL, West J, Haase VH
(2016) Mol Cell Biol 36: 1584-94
MeSH Terms: Animals, Arterial Pressure, Cell Hypoxia, Disease Models, Animal, Hypertension, Pulmonary, Hypoxia-Inducible Factor 1, alpha Subunit, Hypoxia-Inducible Factor-Proline Dioxygenases, Mice, Mutation, Pulmonary Artery, Signal Transduction, Transcription Factors
Show Abstract · Added March 16, 2016
Hypoxia-inducible factors 1 and 2 (HIF-1 and -2) control oxygen supply to tissues by regulating erythropoiesis, angiogenesis and vascular homeostasis. HIFs are regulated in response to oxygen availability by prolyl-4-hydroxylase domain (PHD) proteins, with PHD2 being the main oxygen sensor that controls HIF activity under normoxia. In this study, we used a genetic approach to investigate the endothelial PHD2/HIF axis in the regulation of vascular function. We found that inactivation of Phd2 in endothelial cells specifically resulted in severe pulmonary hypertension (∼118% increase in right ventricular systolic pressure) but not polycythemia and was associated with abnormal muscularization of peripheral pulmonary arteries and right ventricular hypertrophy. Concurrent inactivation of either Hif1a or Hif2a in endothelial cell-specific Phd2 mutants demonstrated that the development of pulmonary hypertension was dependent on HIF-2α but not HIF-1α. Furthermore, endothelial HIF-2α was required for the development of increased pulmonary artery pressures in a model of pulmonary hypertension induced by chronic hypoxia. We propose that these HIF-2-dependent effects are partially due to increased expression of vasoconstrictor molecule endothelin 1 and a concomitant decrease in vasodilatory apelin receptor signaling. Taken together, our data identify endothelial HIF-2 as a key transcription factor in the pathogenesis of pulmonary hypertension.
Copyright © 2016, American Society for Microbiology. All Rights Reserved.
0 Communities
2 Members
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12 MeSH Terms
LMO2 Oncoprotein Stability in T-Cell Leukemia Requires Direct LDB1 Binding.
Layer JH, Alford CE, McDonald WH, Davé UP
(2016) Mol Cell Biol 36: 488-506
MeSH Terms: Adaptor Proteins, Signal Transducing, Amino Acid Sequence, Amino Acid Substitution, Cell Line, DNA-Binding Proteins, Humans, Jurkat Cells, LIM Domain Proteins, Leukemia, T-Cell, Molecular Sequence Data, Mutation, Protein Interaction Domains and Motifs, Protein Interaction Maps, Protein Stability, Proto-Oncogene Proteins, Transcription Factors, Transcriptional Activation
Show Abstract · Added January 26, 2016
LMO2 is a component of multisubunit DNA-binding transcription factor complexes that regulate gene expression in hematopoietic stem and progenitor cell development. Enforced expression of LMO2 causes leukemia by inducing hematopoietic stem cell-like features in T-cell progenitor cells, but the biochemical mechanisms of LMO2 function have not been fully elucidated. In this study, we systematically dissected the LMO2/LDB1-binding interface to investigate the role of this interaction in T-cell leukemia. Alanine scanning mutagenesis of the LIM interaction domain of LDB1 revealed a discrete motif, R(320)LITR, required for LMO2 binding. Most strikingly, coexpression of full-length, wild-type LDB1 increased LMO2 steady-state abundance, whereas coexpression of mutant proteins deficient in LMO2 binding compromised LMO2 stability. These mutant LDB1 proteins also exerted dominant negative effects on growth and transcription in diverse leukemic cell lines. Mass spectrometric analysis of LDB1 binding partners in leukemic lines supports the notion that LMO2/LDB1 function in leukemia occurs in the context of multisubunit complexes, which also protect the LMO2 oncoprotein from degradation. Collectively, these data suggest that the assembly of LMO2 into complexes, via direct LDB1 interaction, is a potential molecular target that could be exploited in LMO2-driven leukemias resistant to existing chemotherapy regimens.
Copyright © 2016, American Society for Microbiology. All Rights Reserved.
0 Communities
2 Members
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17 MeSH Terms
Nerve Growth Factor Regulates Transient Receptor Potential Vanilloid 2 via Extracellular Signal-Regulated Kinase Signaling To Enhance Neurite Outgrowth in Developing Neurons.
Cohen MR, Johnson WM, Pilat JM, Kiselar J, DeFrancesco-Lisowitz A, Zigmond RE, Moiseenkova-Bell VY
(2015) Mol Cell Biol 35: 4238-52
MeSH Terms: Animals, Calcium, Calcium Channels, Cell Line, Tumor, Extracellular Signal-Regulated MAP Kinases, HEK293 Cells, Humans, MAP Kinase Signaling System, Nerve Growth Factor, Neurites, Neurogenesis, Neurons, PC12 Cells, Phosphatidylinositol 3-Kinases, Phosphorylation, RNA Interference, RNA, Small Interfering, Rats, Receptor, trkA, TRPV Cation Channels, rab GTP-Binding Proteins
Show Abstract · Added April 24, 2017
Neurite outgrowth is key to the formation of functional circuits during neuronal development. Neurotrophins, including nerve growth factor (NGF), increase neurite outgrowth in part by altering the function and expression of Ca(2+)-permeable cation channels. Here we report that transient receptor potential vanilloid 2 (TRPV2) is an intracellular Ca(2+)-permeable TRPV channel upregulated by NGF via the mitogen-activated protein kinase (MAPK) signaling pathway to augment neurite outgrowth. TRPV2 colocalized with Rab7, a late endosome protein, in addition to TrkA and activated extracellular signal-regulated kinase (ERK) in neurites, indicating that the channel is closely associated with signaling endosomes. In line with these results, we showed that TRPV2 acts as an ERK substrate and identified the motifs necessary for phosphorylation of TRPV2 by ERK. Furthermore, neurite length, TRPV2 expression, and TRPV2-mediated Ca(2+) signals were reduced by mutagenesis of these key ERK phosphorylation sites. Based on these findings, we identified a previously uncharacterized mechanism by which ERK controls TRPV2-mediated Ca(2+) signals in developing neurons and further establish TRPV2 as a critical intracellular ion channel in neuronal function.
Copyright © 2015, American Society for Microbiology. All Rights Reserved.
0 Communities
1 Members
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21 MeSH Terms
Histone Deacetylase 3 Is Required for Efficient T Cell Development.
Stengel KR, Zhao Y, Klus NJ, Kaiser JF, Gordy LE, Joyce S, Hiebert SW, Summers AR
(2015) Mol Cell Biol 35: 3854-65
MeSH Terms: Animals, CD4 Antigens, CD4-Positive T-Lymphocytes, CD8 Antigens, CD8-Positive T-Lymphocytes, Cell Differentiation, Gene Deletion, Gene Expression Regulation, Developmental, Histone Deacetylases, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Proto-Oncogene Proteins c-bcl-2, Receptors, Antigen, T-Cell, alpha-beta, T-Lymphocytes, bcl-X Protein
Show Abstract · Added September 28, 2015
Hdac3 is a key target for Hdac inhibitors that are efficacious in cutaneous T cell lymphoma. Moreover, the regulation of chromatin structure is critical as thymocytes transition from an immature cell with open chromatin to a mature T cell with tightly condensed chromatin. To define the phenotypes controlled by Hdac3 during T cell development, we conditionally deleted Hdac3 using the Lck-Cre transgene. This strategy inactivated Hdac3 in the double-negative stages of thymocyte development and caused a significant impairment at the CD8 immature single-positive (ISP) stage and the CD4/CD8 double-positive stage, with few mature CD4(+) or CD8(+) single-positive cells being produced. When Hdac3(-/-) mice were crossed with Bcl-xL-, Bcl2-, or TCRβ-expressing transgenic mice, a modest level of complementation was found. However, when the null mice were crossed with mice expressing a fully rearranged T cell receptor αβ transgene, normal levels of CD4 single-positive cells were produced. Thus, Hdac3 is required for the efficient transit from double-negative stage 4 through positive selection.
Copyright © 2015, American Society for Microbiology. All Rights Reserved.
1 Communities
2 Members
0 Resources
18 MeSH Terms
Enhancer of Rudimentary Homolog Affects the Replication Stress Response through Regulation of RNA Processing.
Kavanaugh G, Zhao R, Guo Y, Mohni KN, Glick G, Lacy ME, Hutson MS, Ascano M, Cortez D
(2015) Mol Cell Biol 35: 2979-90
MeSH Terms: Ataxia Telangiectasia Mutated Proteins, Base Sequence, Cell Cycle Proteins, Cell Line, DNA Damage, DNA Repair, DNA Replication, Gene Expression Profiling, HEK293 Cells, Humans, RNA Interference, RNA Splicing, RNA, Small Interfering, Regulatory Sequences, Nucleic Acid, Sequence Analysis, RNA, Signal Transduction, Stress, Physiological, Transcription Factors
Show Abstract · Added February 4, 2016
Accurate replication of DNA is imperative for the maintenance of genomic integrity. We identified Enhancer of Rudimentary Homolog (ERH) using a whole-genome RNA interference (RNAi) screen to discover novel proteins that function in the replication stress response. Here we report that ERH is important for DNA replication and recovery from replication stress. ATR pathway activity is diminished in ERH-deficient cells. The reduction in ATR signaling corresponds to a decrease in the expression of multiple ATR pathway genes, including ATR itself. ERH interacts with multiple RNA processing complexes, including splicing regulators. Furthermore, splicing of ATR transcripts is deficient in ERH-depleted cells. Transcriptome-wide analysis indicates that ERH depletion affects the levels of ∼1,500 transcripts, with DNA replication and repair genes being highly enriched among those with reduced expression. Splicing defects were evident in ∼750 protein-coding genes, which again were enriched for DNA metabolism genes. Thus, ERH regulation of RNA processing is needed to ensure faithful DNA replication and repair.
Copyright © 2015, American Society for Microbiology. All Rights Reserved.
0 Communities
1 Members
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18 MeSH Terms
Regulation of endothelial cell proliferation and vascular assembly through distinct mTORC2 signaling pathways.
Wang S, Amato KR, Song W, Youngblood V, Lee K, Boothby M, Brantley-Sieders DM, Chen J
(2015) Mol Cell Biol 35: 1299-313
MeSH Terms: Adaptor Proteins, Signal Transducing, Animals, Carrier Proteins, Cell Proliferation, Cells, Cultured, Endothelial Cells, Gene Deletion, Human Umbilical Vein Endothelial Cells, Humans, Mechanistic Target of Rapamycin Complex 2, Mice, Multiprotein Complexes, Neovascularization, Physiologic, Phosphorylation, Protein Kinase C-alpha, Proto-Oncogene Proteins c-akt, Rapamycin-Insensitive Companion of mTOR Protein, Regulatory-Associated Protein of mTOR, Signal Transduction, TOR Serine-Threonine Kinases, Vascular Endothelial Growth Factor A
Show Abstract · Added February 15, 2016
Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates a diverse array of cellular processes, including cell growth, survival, metabolism, and cytoskeleton dynamics. mTOR functions in two distinct complexes, mTORC1 and mTORC2, whose activities and substrate specificities are regulated by complex specific cofactors, including Raptor and Rictor, respectively. Little is known regarding the relative contribution of mTORC1 versus mTORC2 in vascular endothelial cells. Using mouse models of Raptor or Rictor gene targeting, we discovered that Rictor ablation inhibited vascular endothelial growth factor (VEGF)-induced endothelial cell proliferation and assembly in vitro and angiogenesis in vivo, whereas the loss of Raptor had only a modest effect on endothelial cells (ECs). Mechanistically, the loss of Rictor reduced the phosphorylation of AKT, protein kinase Cα (PKCα), and NDRG1 without affecting the mTORC1 pathway. In contrast, the loss of Raptor increased the phosphorylation of AKT despite inhibiting the phosphorylation of S6K1, a direct target of mTORC1. Reconstitution of Rictor-null cells with myristoylated AKT (Myr-AKT) rescued vascular assembly in Rictor-deficient endothelial cells, whereas PKCα rescued proliferation defects. Furthermore, tumor neovascularization in vivo was significantly decreased upon EC-specific Rictor deletion in mice. These data indicate that mTORC2 is a critical signaling node required for VEGF-mediated angiogenesis through the regulation of AKT and PKCα in vascular endothelial cells.
Copyright © 2015, American Society for Microbiology. All Rights Reserved.
0 Communities
1 Members
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21 MeSH Terms