Ye-Guang Chen

Tsinghua University, Peping, Beijing, China

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Publications (88)682.15 Total impact

  • Lu Wang, Ye-Guang Chen
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    ABSTRACT: Mesendoderm (ME) refers to the primitive streak in mammalian embryos, which has the ability to further differentiate into mesoderm and endoderm. A better understanding of the regulatory networks of mesendoderm differentiation of embryonic stem (ES) cells would provide important insights on early embryo patterning and a possible guidance for ES applications in regenerative medicine. Studies of developmental biology and embryology have offered a great deal of knowledge about key signaling pathways involved in primitive streak formation. Recently, various chemically-defined recipes have been formulated to induce differentiation of ES cells towards mesendoderm in vitro, which greatly facilitate the elucidation of the regulatory mechanisms of different signals involved in ME specification. Among the extrinsic signals, TGF-β/Activin signaling and Wnt signaling have been shown to be the most critical ones. On another side, intrinsic epigenetic regulation has been indicated to be important in ME determination. In this review, we summarize the current understanding of the extrinsic and intrinsic regulations of ES cells-to-ME differentiation and the crosstalk among them, aiming to get a general overview on ME specification and primitive streak formation. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Journal of Molecular Biology 06/2015; DOI:10.1016/j.jmb.2015.06.013 · 3.96 Impact Factor
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    ABSTRACT: Germ layer induction is one of the earliest events shortly after fertilization that initiates body formation of vertebrate embryos. In Xenopus, the maternally deposited transcriptional factor VegT promotes the expression of zygotic Nodal/Activin ligands that further form a morphogen gradient along the vegetal-animal axis and trigger the induction of the three germ layers. Here we found SCP3 (small C-terminal domain phosphatase 3) is maternally expressed and vegetally enriched in Xenopus embryos and is essential for the timely induction of germ layers. SCP3 is required for the full activation of Nodal/Activin and BMP signals and functions via dephosphorylation of linker regions of R-Smads. Consistently, the linker regions of R-Smads are heavily phosphorylated in fertilized eggs and this phosphorylation is gradually removed when embryos approach the midblastula transition (MBT). Knocking-down of maternal SCP3 attenuates these dephosphorylation events and the activation of Nodal/Activin and BMP signals after MBT. This study thus suggested that the maternal SCP3 serves as a vegetally enriched, intrinsic factor to ensure a prepared status of Smads for their activation by the upcoming ligands during germ layer induction of Xenopus embryos. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    Journal of Biological Chemistry 05/2015; DOI:10.1074/jbc.M115.655605 · 4.60 Impact Factor
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    ABSTRACT: Endocytosis and intracellular sorting of transforming growth factor-β (TGF-β) receptors play an important regulatory role in TGF-β signaling. Two major endocytic pathways, clathrin- and caveolae-mediated endocytosis, have been reported to independently mediate the internalization of TGF-β receptors. In this study, we demonstrate that the clathrin- and caveolae-mediated endocytic pathways can converge during TGF-β receptor endocytic trafficking. By tracking the intracellular dynamics of fluorescently-labeled TGF-β type I receptor (TβRI), we found that after mediating TβRI internalization, certain clathrin-coated vesicles and caveolar vesicles are fused underneath the plasma membrane, forming a novel type of caveolin-1 and clathrin double-positive vesicles. Under the regulation of Rab5, the fused vesicles are targeted to early endosomes and thus deliver the internalized TβRI to the caveolin-1 and EEA1 double-positive early endosomes (caveolin-1-positive early endosomes). We further showed that the caveolin-1-positive early endosomes are positive for Smad3/SARA, Rab11 and Smad7/Smurf2, and may act as a multifunctional device for TGF-β signaling and TGF-β receptor recycling and degradation. Therefore, these findings uncover a novel scenario of endocytosis, the direct fusion of clathrin-coated and caveolae vesicles during TGF-β receptor endocytic trafficking, which leads to the formation of the multifunctional sorting device, caveolin-1-positive early endosomes, for TGF-β receptors.Cell Research advance online publication 22 May 2015; doi:10.1038/cr.2015.60.
    Cell Research 05/2015; 25(6). DOI:10.1038/cr.2015.60 · 11.98 Impact Factor
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    ABSTRACT: Lgr5+ stem cells are crucial to gut epithelium homeostasis, and therapies targeting these cells hold promise for treatment of gastrointestinal diseases. Here we report that the non-muscle-myosin-II (NMII) heavy chain Myh9 accumulates at epithelial injury sites in mice distal colon treated with dextran sulphate sodium (DSS). Gut-epithelium-specific Myh9 monoallelic deletion alleviates DSS-induced colonic crypt damage and acute colitis. Consistently, the NMII inhibitor blebbistatin can improve the survival of Lgr5+ stem cells and the growth of Lgr5 organoids. Mechanistically, inhibition of NMII by blebbistatin or Myh9 monoallelic deletion activates Akt through Rac1 and PAK1, which is essential for the survival and pluripotency of Lgr5+ cells. These results establish a critical role of the Myh9-Rac1-PAK1-Akt pathway in the maintenance of Lgr5+ stem cells. As blebbistatin can mitigate DSS-induced colitis and preserve Lgr5+ colonic stem cells in vivo, our findings provide a potential therapeutic intervention of gastrointestinal epithelium injury and degenerative diseases.
    Nature Communications 05/2015; 6:7166. DOI:10.1038/ncomms8166 · 10.74 Impact Factor
  • Zhen Qi, Ye-Guang Chen
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    ABSTRACT: The remarkable ability of rapid self-renewal makes the intestinal epithelium an ideal model for the study of adult stem cells. The intestinal epithelium is organized into villus and crypt, and a group of intestinal stem cells located at the base of crypt are responsible for this constant self-renewal throughout the life. Identification of the intestinal stem cell marker Lgr5, isolation and in vitro culture of Lgr5+ intestinal stem cells and the use of transgenic mouse models have significantly facilitated the studies of intestinal stem cell homeostasis and differentiation, therefore greatly expanding our knowledge of the regulatory mechanisms underlying the intestinal stem cell fate determination. In this review, we summarize the current understanding of how signals of Wnt, BMP, Notch and EGF in the stem cell niche modulate the intestinal stem cell fate.
    Science China. Life sciences 05/2015; DOI:10.1007/s11427-015-4859-7 · 1.51 Impact Factor
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    ABSTRACT: Autophagy is a regulated process that sequesters and transports cytoplasmic materials such as protein aggregates via autophagosomes to lysosomes for degradation. Dapper1 (Dpr1), an interacting protein of Dishevelled (Dvl), antagonizes Wnt signaling by promoting Dvl degradation via lysosomes. However, the mechanism is unclear. Here, we show that Dpr1 promotes the Von Hippel-Lindau tumor suppressor (VHL)-mediated ubiquitination of Dvl2 and its autophagic degradation. Knockdown of Dpr1 decreases the interaction between Dvl2 and pVHL, resulting in reduced ubiquitination of Dvl2. Dpr1-mediated autophagic degradation of Dvl2 depends on Dvl2 aggregation. Moreover, the aggregate-prone proteins Dvl2, p62 and the hungtingtin mutant Htt103Q promote autophagy in a Dpr1-dependent manner. These protein aggregates enhance the Beclin1-Vps34 interaction and Atg14L puncta formation, indicating that aggregated proteins stimulate autophagy initiation. Ubiquitination is not essential for the aggregates-induced autophagy initiation as inhibition of the ubiquitin-activation E1 enzyme activity did not block the aggregates-induced Atg14L puncta formation. Our findings suggest that Dpr1 promotes the ubiquitination of Dvl2 by pVHL and mediates the protein aggregates-elicited autophagy initiation. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    Journal of Biological Chemistry 03/2015; 290(19). DOI:10.1074/jbc.M115.654590 · 4.60 Impact Factor
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    ABSTRACT: Epithelial-mesenchymal transition (EMT) is a fundamental process in embryonic development and organ formation. Aberrant regulation of EMT often leads to tumor progression. Changes in cell-surface sialylation have recently been implicated in mediating EMT. Herein we report the visualization of dynamic changes of sialylation and glycoproteomic analysis of newly synthesized sialylated proteins in EMT by metabolic labeling of sialylated glycans with azides, followed by click-labeling with fluorophores and affinity tags. We discovered that sialylation was downregulated during EMT, but then reverted and upregulated in the mesenchymal state after EMT, accompanied by mRNA expression level changes of genes involved in the sialic acid biosynthesis. Quantitative proteomic analysis identified a list of sialylated proteins whose biosynthesis was dynamically regulated during EMT. Sialylation of cell-surface adherent receptor integrin β4 was found to be downregulated, which may regulate integrin functions during EMT. Furthermore, a global sialylation inhibitor was used to probe the functional role of sialylation during EMT. We found that inhibition of sialylation promoted EMT. Taken together, our findings suggest the important role of sialylation in regulating EMT and imply its possible function in related pathophysiological events, such as cancer metastasis. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    Journal of Biological Chemistry 03/2015; 290(19). DOI:10.1074/jbc.M115.636969 · 4.60 Impact Factor
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    ABSTRACT: Receptor-mediated signal transduction modulates complex cellular behaviours such as cell growth, migration and differentiation. Although photoactivatable proteins have emerged as a powerful tool for controlling molecular interactions and signalling cascades at precise times and spaces using light, many of these light-sensitive proteins are activated by ultraviolent or visible light, which has limited tissue penetration. Here, we report a single-walled carbon nanotube (SWCNT)-assisted approach that enables near-infrared light-triggered activation of transforming growth factor β (TGF-β) signal transduction, an important signalling pathway in embryonic development and cancer progression. The protein complex of TGF-β and its latency-associated peptide is conjugated onto SWCNTs, where TGF-β is inactive. Upon near-infrared irradiation, TGF-β is released through the photothermal effect of SWCNTs and becomes active. The released TGF-β activates downstream signal transduction in live cells and modulates cellular behaviours. Furthermore, preliminary studies show that the method can be used to mediate TGF-β signalling in living mice.
    Nature Nanotechnology 03/2015; 10(5). DOI:10.1038/nnano.2015.28 · 33.27 Impact Factor
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    ABSTRACT: Transforming growth factor β receptor II (Tβ RII) is synthesized in the cytoplasm and then transported to the plasma membrane of cells to fulfil its signalling duty. Here, we applied live-cell fluorescence imaging techniques, in particular quasi-total internal reflection fluorescence microscopy, to imaging fluorescent protein-tagged Tβ RII and monitoring its secretion process. We observed punctuate-like Tβ RII-containing post-Golgi vesicles formed in MCF7 cells. Single-particle tracking showed that these vesicles travelled along the microtubules at an average speed of 0.51 μm/s. When stimulated by TGF-β ligand, these receptor-containing vesicles intended to move towards the plasma membrane. We also identified several factors that could inhibit the formation of such post-Golgi vesicles. Although the inhibitory mechanisms still remain unknown, the observed characteristics of Tβ RII-containing vesicles provide new information on intracellular Tβ RII transportation. It also renders Tβ RII a good model system for studying post-Golgi vesicle-trafficking and protein transportation. (© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim).
    Journal of Biophotonics 10/2014; 7(10). DOI:10.1002/jbio.201300020 · 3.86 Impact Factor
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    ABSTRACT: Wnt/β-catenin signaling via the β-catenin/TCF complex plays crucial roles in tissue homeostasis. Wnt stimulated β-catenin/TCF complex accumulation in the nucleus regulates cell survival, proliferation, and differentiation through the transcription of target genes. Compared with those in G1, LRP6 receptor activation and cytosolic β-catenin are both up-regulated in G2 cells. However, accumulation of the Wnt pathway negative regulator, AXIN2, also occurs in this phase. Therefore, it is unclear whether Wnt signaling is active in G2 phase cells. Here, we established a bimolecular fluorescence complementation (BiFC) biosensor system for the direct visualization of β-catenin/TCF interaction in living cells. Using the BiFC biosensor and co-immunoprecipitation experiments, we demonstrated the nucleus-localized β-catenin/TCF complex increases during the S and G2 phases, and declines in the next G1 phase. Accordingly, a subset of Wnt target genes was transcribed by the β-catenin/TCF complex during both S and G2 phases. In contrast, transient inhibition of this complex disturbed both cell survival and G2/M progression. Our results suggest that in S-G2 phase cells, Wnt/β-catenin signaling is highly active and functions to ensure cell survival and cell-cycle progression.
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    ABSTRACT: Autophagy is an intracellular degradation process to clear up aggregated proteins or aged and damaged organelles. The Beclin1-Vps34-Atg14L complex is essential for autophagosome formation. However, how the complex formation is regulated is unclear. Here, we show that Dapper1 (Dpr1) acts as a critical regulator of the Beclin1-Vps34-Atg14L complex to promote autophagy. Dpr1 ablation in the central nervous system results in motor coordination defect and accumulation of p62 and ubiquitinated proteins. Dpr1 increases autophagosome formation as indicated by elevated puncta formation of LC3, Atg14L and DFCP1 (Double FYVE-containing protein 1). Conversely, loss of Dpr1 impairs LC3 lipidation and causes p62/SQSTM1 accumulation. Dpr1 directly interacts with Beclin1 and Atg14L and enhances the Beclin1-Vps34 interaction and Vps34 activity. Together, our findings suggest that Dpr1 enhances the Atg14L-Beclin1-Vps34 complex formation to drive autophagy.Cell Research advance online publication 1 July 2014; doi:10.1038/cr.2014.84.
    Cell Research 07/2014; 24(8). DOI:10.1038/cr.2014.84 · 11.98 Impact Factor
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    ABSTRACT: Development of animal embryos before zygotic genome activation at the midblastula transition (MBT) is essentially supported by egg-derived maternal products. Nodal proteins are crucial signals for mesoderm and endoderm induction after the MBT. It remains unclear which maternal factors activate zygotic expression of nodal genes in the ventrolateral blastodermal margin of the zebrafish blastulas. In this study, we show that loss of maternal Eomesodermin a (Eomesa), a T-box transcription factor, impairs zygotic expression of the nodal genes ndr1 and ndr2 as well as mesodermal and endodermal markers, indicating an involvement in mesendoderm induction. Maternal Eomesa is also required for timely zygotic expression of the transcription factor gene mxtx2, a regulator of nodal gene expression. Eomesa directly binds to the Eomes-binding sites in the promoter or enhancer of ndr1, ndr2, and mxtx2 to activate their transcription. Furthermore, human and mouse Nodal genes are also regulated by Eomes. Transfection of zebrafish eomesa into murine embryonic stem cells promotes mesendodermal differentiation with constant higher levels of endogenous Nodal expression, suggesting a conserved function of Eomes. Taken together, our findings reveal a conserved role of maternal T-box transcription factors in regulating nodal gene expression and mesendoderm induction in vertebrate embryos.
    Journal of Molecular Cell Biology 06/2014; 6(4). DOI:10.1093/jmcb/mju028 · 8.43 Impact Factor
  • Yan Zhang, Yi Ding, Ye-Guang Chen, Qinghua Tao
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    ABSTRACT: During the early vertebrate body plan formation, convergent extension (CE) of dorsal mesoderm and neurectoderm is coordinated by the evolutionarily conserved non-canonical Wnt/PCP signaling. Dishevelled (Dvl), a key mediator of Wnt/PCP signaling, is essential for the medial-lateral polarity formation in the cells undergoing convergent extension movements. NEDD4L, a highly conserved HECT type E3 ligase, has been reported to regulate the stability of multiple substrates including Dvl2. Here we demonstrate that NEDD4L is required for the cellular polarity formation and convergent extension in the early Xenopus embryos. Depletion of NEDD4L in early Xenopus embryos results in the loss of mediolateral polarity of the convergent-extending mesoderm cells and the shortened body axis, resembling those defects caused by the disruption of non-canonical Wnt signaling. Depletion of xNEDD4L also blocks the elongation of the animal explants in response to endogenous mesoderm inducing signals and partially compromises the expression of Brachyury. Importantly, reducing Dvl2 expression can largely rescue the cellular polarity and convergent extension defects in NEDD4L-depleted embryos and explants. Together with the data that NEDD4L reduces Dvl2 protein expression in the frog embryos, our findings suggest that regulation of Dvl protein levels by NEDD4L is essential for convergent extension during early Xenopus embryogenesis.
    Developmental Biology 05/2014; DOI:10.1016/j.ydbio.2014.05.003 · 3.64 Impact Factor
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    Bing Zhao, Ye-Guang Chen
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    ABSTRACT: Transforming growth factor-β (TGF-β) signaling regulates diverse cellular processes, including cell proliferation, differentiation, apoptosis, cell plasticity, and migration. TGF-β signaling can be mediated by Smad proteins or other signaling proteins such as MAP kinases and Akt. TGF-β signaling is tightly regulated at different levels along the pathways to ensure its proper physiological functions in different cells and tissues. Deregulation of TGF-β signaling has been associated with various kinds of diseases, such as cancer and tissue fibrosis. This paper focuses on our recent work on regulation of TGF-β signaling.
    01/2014; 2014:874065. DOI:10.1155/2014/874065
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    ABSTRACT: The zinc finger transcription factor Smad-interacting protein-1 (Sip1; Zeb2, Zfhx1b) plays an important role during vertebrate embryogenesis in various tissues and differentiating cell types, and during tumorigenesis. Previous biochemical analysis suggests that interactions with several partner proteins, including TGFβ family receptor-activated Smads, regulate the activities of Sip1 in the nucleus both as a DNA-binding transcriptional repressor and activator. Using a peptide aptamer approach we mapped in Sip1 its Smad-binding domain (SBD), initially defined as a segment of 51 amino acids, to a shorter stretch of 14 amino acids within this SBD. Modelling suggests that this short SBD stretch is part of an extended α-helix that may fit the binding to a hydrophobic corridor within the MH2 domain of activated Smads. Four amino acids (two polar Q residues and two non-polar V residues) that form the tandem repeat (QxVx)2 in this 14-residue stretch were found to be crucial for binding to both TGFβ/Nodal/Activin-Smads and BMP-Smads. A full-length Sip1 with collective mutation of these Q and V residues (to A) no longer binds to Smads, while it retains its binding activity to its cognate bipartite target DNA sequence. This missense mutant Sip1(AxAx)2 provides a new molecular tool to identify SBD (in)dependent target genes in Sip1-controlled TGFβ and/or BMP (de)regulated cellular, developmental and pathological processes.
    PLoS ONE 10/2013; 8(10):e76733. DOI:10.1371/journal.pone.0076733 · 3.53 Impact Factor
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    ABSTRACT: The DNA damage checkpoint is tightly controlled. After its activation, the checkpoint machinery is inactivated once lesions are repaired, or undergoes adaptation if the DNA damage is unable to be repaired. Protein acetylation has been shown to play an important role in DNA damage checkpoint activation. However, the role of acetylation in checkpoint inactivation is unclear. Here we show that the histone deacetylase Rpd3-mediated deacetylation of Rad53 plays an important role in checkpoint adaptation. Deletion of Rpd3 or inhibition of its activity impairs adaptation. RPD3 deletion also leads to a higher acetylation level and enhanced kinase activity of Rad53. Substitution of two major acetylation sites of Rad53 with arginine reduces its activity, and further suppresses the adaptation defect of rpd3Δ cells, indicating that Rpd3 facilitates adaptation by preventing Rad53 over-activation. Similar to its role in adaptation, deletion of RPD3 or inhibiting its activity also suppressed checkpoint recovery. Altogether, our findings reveal an important role of Rpd3 in promoting checkpoint adaptation via deacetylation and inhibition of Rad53.
    Molecular and Cellular Biology 08/2013; DOI:10.1128/MCB.00618-13 · 5.04 Impact Factor
  • Wei Zuo, Ye-Guang Chen
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    ABSTRACT: In hematopoietic system, hematopoietic stem cells (HSCs) are characterized by their self-renewal and multilineage differentiation capability. The abnormal behavior of HSCs causes emergence and progression of leukemia and other hematopoietic malignancies. Transforming growth factor β (TGF-β) is a multipotent factor which impacts the diverse fates of HSCs, including proliferation, self-renewal, differentiation, apoptosis, and mobilization from the niche. TGF-β signaling is finely controlled, and its deregulation is associated to leukemia development. In recent years, using genetically modified mice and hematopoietic stem cell transplantation system, the in vivo functions of TGF-β signaling in hematopoietic system have been greatly appreciated. This review summarizes the recent development on the role of TGF-β signaling in HSC fate decision and leukemia development.
    08/2013; 1. DOI:10.1166/ch.2013.1008
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    ABSTRACT: Smad2/3-mediated transforming growth factor β signalling and the Ras-Raf-Mek-Erk cascade have important roles in stem cell and development and tissue homeostasis. However, it remains unknown whether Raf kinases directly crosstalk with Smad2/3 signalling and how this would regulate embryonic development. Here we show that Araf antagonizes mesendoderm induction and patterning activity of Nodal/Smad2 signals in vertebrate embryos by directly inhibiting Smad2 signalling. Knockdown of araf in zebrafish embryos leads to an increase of activated Smad2 with a decrease in linker phosphorylation; consequently, the embryos have excess mesendoderm precursors and are dorsalized. Mechanistically, Araf physically binds to and phosphorylates Smad2 in the linker region with S253 being indispensable in a Mek/Erk-independent manner, thereby attenuating Smad2 signalling by accelerating degradation of activated Smad2. Our findings open avenues for investigating the potential significance of Raf regulation of transforming growth factor β signalling in versatile biological and pathological processes in the future.
    Nature Communications 04/2013; 4:1728. DOI:10.1038/ncomms2762 · 10.74 Impact Factor
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    ABSTRACT: Wnt/β-catenin signaling plays key roles in embryonic development and tissue homeostasis. Dapper3/Dact3, one of the three members of the Dapper gene family, is transcriptionally repressed in colorectal cancer and may function as a negative regulator of Wnt/β-catenin signaling. To investigate its physiological functions, we generated a mouse strain harboring conditional null alleles of Dapper3 (Dapper3flox/flox), and homozygous Dapper3 deficient (Dapper3-/-) mice were produced after crossing with EIIa-cre transgenic mice. We found that Dapper3 is not essential for mouse embryogenesis, postnatal survival and reproduction. However, adult Dapper3-/- mice exhibited a mild reduction in body weight compared with their wild-type littermates, suggesting a functional role of Dapper3 in postnatal growth. To investigate the role of Dapper3 in renal fibrosis, we employed the unilateral ureteral obstruction (UUO) model. Dapper3 mRNA expression was upregulated in kidney after UUO. Loss of the Dapper3 gene enhanced myofibroblast activation and extracellular matrix overproduction in the obstructed kidney. Moreover, this aggravated fibrotic phenotype was accompanied with accumulation of Dishevelled2 and β-catenin proteins and activation of Wnt targeted fibrotic genes. In primary renal tubular cells, Dapper3 inhibits Wnt induced epithelial-to-mesenchymal transition. Consistently, Dapper3 interacted with and downregulated Dishevelled2 protein, and attenuated the Wnt-responsive Topflash reporter expression. These findings together suggest that Dapper3 antagonizes the fibrotic actions of Wnt signaling in kidney.
    Journal of Biological Chemistry 04/2013; DOI:10.1074/jbc.M113.458448 · 4.60 Impact Factor
  • Cell Research 02/2013; DOI:10.1038/cr.2013.30 · 11.98 Impact Factor

Publication Stats

2k Citations
682.15 Total Impact Points

Institutions

  • 2004–2015
    • Tsinghua University
      • School of Life Sciences
      Peping, Beijing, China
    • Chinese Center For Disease Control And Prevention
      • Institute for Viral Disease Control and Prevention
      Peping, Beijing, China
  • 2006–2012
    • Shanghai Institutes for Biological Sciences
      Shanghai, Shanghai Shi, China
  • 2011
    • China-Japan Friendship Hospital
      Peping, Beijing, China
  • 2007–2008
    • National Tsing Hua University
      Hsin-chu-hsien, Taiwan, Taiwan
    • Baylor College of Medicine
      • Department of Molecular & Cellular Biology
      Houston, Texas, United States
  • 2002
    • The Rockefeller University
      New York, New York, United States