PubMed Health⌕ Search

Biomedical subjects

Ye-Guang Chen

Publications and source records attributed to Ye-Guang Chen.

17 recordsLinked to original sources
PubMed2006

The evolutionally conserved activity of Dapper2 in antagonizing TGF-beta signaling.

Dapper1 and Dapper2, two divergent members of the Dapper family, have been suggested to modulate Wnt and TGF-beta/Nodal signaling in Xenopus and zebrafish. To get a better understanding of Dapper function in mammals, we have cloned the mouse ortholog of zebrafish Dapper2, mDpr2 and investigated its function in regulating TGF-beta signaling activity. Here, we showed that, like zebrafish Dapper2, overexpression of mDpr2 inhibited the TGF-beta-induced expression of the Smad-responsive reporters and targeted TGF-beta type I receptor ALK5 for degradation in mammalian cells. Overexpression of mDpr2 in the zebrafish embryos led to a decrease in expression of the mesoderm marker no tail and goosecoid at the shield stage and eye fusion later, implying that mDpr2 may have an intrinsic in vivo activity similar to fish Dapper2 activity. The expression of mDpr2 was detected throughout the epiblast around the onset of gastrulation and in somites, the neural tube and gut at later stages in mouse embryos, implying a role in early embryonic development. Our data indicate that the function of Dpr2 as a negative regulator of the TGF-beta/Nodal signal pathway is evolutionally conserved, at least in part, in fish and mammals.

Animals↗
PubMed2006

Identification of the proliferation/differentiation switch in the cellular network of multicellular organisms.

The protein-protein interaction networks, or interactome networks, have been shown to have dynamic modular structures, yet the functional connections between and among the modules are less well understood. Here, using a new pipeline to integrate the interactome and the transcriptome, we identified a pair of transcriptionally anticorrelated modules, each consisting of hundreds of genes in multicellular interactome networks across different individuals and populations. The two modules are associated with cellular proliferation and differentiation, respectively. The proliferation module is conserved among eukaryotic organisms, whereas the differentiation module is specific to multicellular organisms. Upon differentiation of various tissues and cell lines from different organisms, the expression of the proliferation module is more uniformly suppressed, while the differentiation module is upregulated in a tissue- and species-specific manner. Our results indicate that even at the tissue and organism levels, proliferation and differentiation modules may correspond to two alternative states of the molecular network and may reflect a universal symbiotic relationship in a multicellular organism. Our analyses further predict that the proteins mediating the interactions between these modules may serve as modulators at the proliferation/differentiation switch.

Animals↗
PubMed2006

MCP-1 mediates TGF-beta-induced angiogenesis by stimulating vascular smooth muscle cell migration.

Transforming growth factor-beta (TGF-beta) and its signaling mediators play crucial roles in vascular formation. Our previous microarray analysis identified monocyte chemoattractant protein-1 (MCP-1) as a TGF-beta target gene in endothelial cells (ECs). Here, we report that MCP-1 mediates the angiogenic effect of TGF-beta by recruiting vascular smooth muscle cells (VSMCs) and mesenchymal cells toward ECs. By using a chick chorioallantoic membrane assay, we show that TGF-beta promotes the formation of new blood vessels and this promotion is attenuated when MCP-1 activity is blocked by its neutralizing antibody. Wound healing and transwell assays established that MCP-1 functions as a chemoattractant to stimulate migration of VSMCs and mesenchymal 10T1/2 cells toward ECs. Furthermore, the conditioned media from TGF-beta-treated ECs stimulate VSMC migration, and inhibition of MCP-1 activity attenuates TGF-beta-induced VSMC migration toward ECs. Finally, we found that MCP-1 is a direct gene target of TGF-beta via Smad3/4. Taken together, our findings suggest that MCP-1 mediates TGF-beta-stimulated angiogenesis by enhancing migration of mural cells toward ECs and thus promoting the maturation of new blood vessels.

Cell Communication↗
PubMed2006

PPM1A functions as a Smad phosphatase to terminate TGFbeta signaling.

TGFbeta signaling controls diverse normal developmental processes and pathogenesis of diseases including cancer and autoimmune and fibrotic diseases. TGFbeta responses are generally mediated through transcriptional functions of Smads. A key step in TGFbeta signaling is ligand-induced phosphorylation of receptor-activated Smads (R-Smads) catalyzed by the TGFbeta type I receptor kinase. However, the potential of Smad dephosphorylation as a regulatory mechanism of TGFbeta signaling and the identity of Smad-specific phosphatases remain elusive. Using a functional genomic approach, we have identified PPM1A/PP2Calpha as a bona fide Smad phosphatase. PPM1A dephosphorylates and promotes nuclear export of TGFbeta-activated Smad2/3. Ectopic expression of PPM1A abolishes TGFbeta-induced antiproliferative and transcriptional responses, whereas depletion of PPM1A enhances TGFbeta signaling in mammalian cells. Smad-antagonizing activity of PPM1A is also observed during Nodal-dependent early embryogenesis in zebrafish. This work demonstrates that PPM1A/PP2Calpha, through dephosphorylation of Smad2/3, plays a critical role in terminating TGFbeta signaling.

Active Transport, Cell Nucleus↗
PubMed2006

Activation and roles of ALK4/ALK7-mediated maternal TGFbeta signals in zebrafish embryo.

Activin, Nodal, and Vg1, members of the transforming growth factor beta (TGFbeta) superfamily, transduce signal through type I receptors ALK4 or ALK7 and play important roles in mesoderm induction and patterning during vertebrate embryogenesis. However, the timing and magnitude of the ALK4/ALK7-mediated maternal TGFbeta signals are not clear. SB-431542 is identified as an inhibitor of the ALK4/ALK5/ALK7-mediated TGFbeta signals and its specificity in vertebrate embryos has not been reported. We demonstrate that SB-431542 is able to specifically and reproducibly block the Smad2/3-mediated TGFbeta signals in zebrafish embryo. Embryos exposed to SB-431542 exhibit various defects phenocopying Nodal-deficient mutants. SB-431542 treatments starting at different cell cycles before the midblastula transition lead to different degrees of developmental defects in mesoderm induction and patterning, suggesting that maternal TGFbeta signals are activated right after fertilization and required for mesoderm formation and patterning.

Activin Receptors↗
PubMed2006

Cell aggregation-induced FGF8 elevation is essential for P19 cell neural differentiation.

FGF8, a member of the fibroblast growth factor (FGF) family, has been shown to play important roles in different developing systems. Mouse embryonic carcinoma P19 cells could be induced by retinoic acid (RA) to differentiate into neuroectodermal cell lineages, and this process is cell aggregation dependent. In this report, we show that FGF8 expression is transiently up-regulated upon P19 cell aggregation, and the aggregation-dependent FGF8 elevation is pluripotent stem cell related. Overexpressing FGF8 promotes RA-induced monolayer P19 cell neural differentiation. Inhibition of FGF8 expression by RNA interference or blocking FGF signaling by the FGF receptor inhibitor, SU5402, attenuates neural differentiation of the P19 cell. Blocking the bone morphogenetic protein (BMP) pathway by overexpressing Smad6 in P19 cells, we also show that FGF signaling plays a BMP inhibition-independent role in P19 cell neural differentiation.

Animals↗
PubMed2006

Axin is a scaffold protein in TGF-beta signaling that promotes degradation of Smad7 by Arkadia.

TGF-beta signaling involves a wide array of signaling molecules and multiple controlling events. Scaffold proteins create a functional proximity of signaling molecules and control the specificity of signal transduction. While many components involved in the TGF-beta pathway have been elucidated, little is known about how those components are coordinated by scaffold proteins. Here, we show that Axin activates TGF-beta signaling by forming a multimeric complex consisting of Smad7 and ubiquitin E3 ligase Arkadia. Axin depends on Arkadia to facilitate TGF-beta signaling, as their small interfering RNAs reciprocally abolished the stimulatory effect on TGF-beta signaling. Specific knockdown of Axin or Arkadia revealed that Axin and Arkadia cooperate with each other in promoting Smad7 ubiquitination. Pulse-chase experiments further illustrated that Axin significantly decreased the half-life of Smad7. Axin also induces nuclear export of Smad7. Interestingly, Axin associates with Arkadia and Smad7 independently of TGF-beta signal, in contrast to its transient association with inactive Smad3. However, coexpression of Wnt-1 reduced Smad7 ubiquitination by downregulating Axin levels, underscoring the importance of Axin as an intrinsic regulator in TGF-beta signaling.

Active Transport, Cell Nucleus↗
PubMed2006

Dapper 1 antagonizes Wnt signaling by promoting dishevelled degradation.

Wnt signaling plays pivotal roles in the regulation of embryogenesis and cancer development. Xenopus Dapper (Dpr) was identified as an interacting protein for Dishevelled (Dvl), a Wnt signaling mediator, and modulates Wnt signaling. However, it is largely unclear how Dpr regulates Wnt signaling. Here, we present evidence that human Dpr1, the ortholog of Xenopus Dpr, inhibits Wnt signaling. We have identified the regions responsible for the Dpr-Dvl interaction in both proteins and found that the interaction interface is formed between the DEP (Dishevelled, Egl-10, and pleckstrin) domain of Dvl and the central and the C-terminal regions of Dpr1. The inhibitory function of human Dpr1 requires both its N and C terminus. Overexpression of the C-terminal region corresponding to the last 225 amino acids of Dpr1, in contrast to wild-type Dpr1, enhances Wnt signaling, suggesting a dominant negative function of this region. Furthermore, we have shown that Dpr1 induces Dvl degradation via a lysosome inhibitor-sensitive and proteasome inhibitor-insensitive mechanism. Knockdown of Dpr1 by RNA interference up-regulates endogenous Dvl2 protein. Taken together, our data indicate that the inhibitory activity of Dpr on Wnt signaling is conserved from Xenopus to human and that Dpr1 antagonizes Wnt signaling by inducing Dvl degradation.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Distinct regulation of gene expression in human endothelial cells by TGF-beta and its receptors.

Transforming growth factor beta (TGF-beta) and its signaling mediators play essential roles in angiogenesis-formation of new blood vessels, as evidenced by targeted gene disruption in mice and their mutations in human vascular dysplasia. However, little is known about the molecular basis of TGF-beta function in vascular formation. To study the function of TGF-beta signaling in angiogenesis and to elucidate the signaling specificity of TGF-beta receptors at the gene transcriptional level, we analyzed the expression profile of the genes regulated by TGF-beta and its type I receptors ALK1 and ALK5 in human microvessel endothelial cells (ECs). Global change of gene expression profiles was examined by microarray and RT-PCR analyses in the ECs treated with TGF-beta1 or by adenoviral expression of the active ALK1 or ALK5. We found that the profiles of the genes regulated by TGF-beta, ALK1 and ALK5 are distinct from each other, although some of genes are modulated by all of them. TGF-beta regulated far more genes than ALK1 and ALK5 did. ALK1 enhanced the formation of tube-like structures of ECs, while ALK5 stimulates EC aggregation. Our results suggest that ALK1 appears to have important functions in regulating proliferation of ECs, whereas ALK5 tends to modulate cell-cell interaction and cell adhesion and extracellular matrix remodeling.

Activin Receptors, Type I↗
PubMed2006

Tob1 controls dorsal development of zebrafish embryos by antagonizing maternal beta-catenin transcriptional activity.

Maternal beta-catenin and Nodal signals are essential for the formation of the dorsal organizer, which, in turn, induces neural and other dorsal tissue development in vertebrate embryos. Tob (Transducer of ErbB2) proteins possess antiproliferative properties and are known to influence BMP signaling, but their relationship to other signaling pathways and to embryonic patterning in general was unclear. In this study, we demonstrate that zebrafish tob1a is required for correct dorsoventral patterning. Mechanistically, Tob1a inhibits beta-catenin transcriptional activity by physically associating with beta-catenin and preventing the formation of beta-catenin/LEF1 complexes. Although Tob1a can also inhibit the transcriptional activity of the Nodal effector Smad3, its role in limiting dorsal development is executed primarily by antagonizing the beta-catenin signal. We further demonstrate that Tob family members across species share similar biochemical properties and biological activities.

Animals↗
PubMed2006

Activin signaling and its role in regulation of cell proliferation, apoptosis, and carcinogenesis.

Activins, cytokine members of the transforming growth factor-beta superfamily, have various effects on many physiological processes, including cell proliferation, cell death, metabolism, homeostasis, differentiation, immune responses endocrine function, etc. Activins interact with two structurally related serine/threonine kinase receptors, type I and type II, and initiate downstream signaling via Smads to regulate gene expression. Understanding how activin signaling is controlled extracellularly and intracellularly would not only lead to more complete understanding of cell growth and apoptosis, but would also provide the basis for therapeutic strategies to treat cancer and other related diseases. This review focuses on the recent progress on activin-receptor interactions, regulations of activin signaling by ligand-binding proteins, receptor-binding proteins, and nucleocytoplasmic shuttling of Smad proteins.

Activin Receptors↗
PubMed2005

Functional analysis of mutations in the kinase domain of the TGF-beta receptor ALK1 reveals different mechanisms for induction of hereditary hemorrhagic telangiectasia.

Genetic studies in mouse and zebrafish have established the importance of activin receptor-like kinase 1 (ALK1) in formation and remodeling of blood vessels. Single-allele mutations in the ALK1 gene have been linked to the human type 2 hereditary hemorrhagic telangiectasia (HHT2). However, how these ALK1 mutations contribute to this disorder remains unclear. To explore the mechanism underlying effect of the HHT-related ALK1 mutations on receptor activity, we generated 11 such mutants and investigated their signaling activities using reporter assay in mammalian cells and examined their effect on zebrafish embryogenesis. Here we show that some of the HHT2-related mutations generate a dominant-negative effect whereas the others give rise to a null phenotype via loss of protein expression or receptor activity. These data indicate that loss-of-function mutations in a single allele of the ALK1 locus are sufficient to contribute to defects in maintaining endothelial integrity.

Activin Receptors, Type I↗
PubMed2004

Zebrafish Dpr2 inhibits mesoderm induction by promoting degradation of nodal receptors.

Nodal proteins, members of the transforming growth factor-beta (TGFbeta) superfamily, have been identified as key endogenous mesoderm inducers in vertebrates. Precise control of Nodal signaling is essential for normal development of embryos. Here, we report that zebrafish dapper2 (dpr2) is expressed in mesoderm precursors during early embryogenesis and is positively regulated by Nodal signals. In vivo functional studies in zebrafish suggest that Dpr2 suppresses mesoderm induction activities of Nodal signaling. Dpr2 is localized in late endosomes, binds to the TGFbeta receptors ALK5 and ALK4, and accelerates lysosomal degradation of these receptors.

Activin Receptors, Type I↗
PubMed2004

Inhibition of severe acute respiratory syndrome virus replication by small interfering RNAs in mammalian cells.

Severe acute respiratory syndrome (SARS) is an acute respiratory infectious disease that spread worldwide in early 2003. The cause was determined as a novel coronavirus (CoV), SARS-associated CoV (SARS-CoV), with a single-stranded, plus-sense RNA. To date, no effective specific treatment has been identified. To exploit the possibility of using RNA interference as a therapeutic approach to fight the disease, plasmid-mediated small interfering RNAs (siRNAs) were generated to target the SARS-CoV genome. The expression of siRNAs from two plasmids, which specifically target the viral RNA polymerase, effectively blocked the cytopathic effects of SARS-CoV on Vero cells. These two plasmids also inhibited viral replication as shown by titer assays and by an examination of viral RNA and protein levels. Thus, our results demonstrated the feasibility of developing siRNAs as effective anti-SARS drugs.

Animals↗
PubMed2002

Transforming growth factor beta activates Smad2 in the absence of receptor endocytosis.

Like many other cell surface receptors, transforming growth factor beta (TGF-beta) receptors are internalized upon ligand stimulation. Given that the signaling-facilitating molecules Smad anchor for receptor activation (SARA) and Hrs are mainly localized in early endosomes, it was unclear whether receptor internalization is required for Smad2 activation. Using reversible biotin labeling, we directly monitored internalization of the TGF-beta type I receptor. Our data indicate that TGF-beta type I receptor is endocytosed via a clathrin-dependent mechanism and is effectively blocked by depletion of intracellular potassium or by expression of a mutant dynamin (K44A). However, blockage of receptor endocytosis by these two means has no effect on TGF-beta-mediated Smad2 activation. Furthermore, TGF-beta-induced Smad2 activation was unaffected by inhibition of hVPS34 activity with wortmannin or inhibitory anti-hVPS34 antibodies. Finally, we demonstrated that Smad2 interacted with cell surface receptors and that a SARA binding-deficient Smad2 mutant was phosphorylated by the receptors. Thus, our findings suggest that receptor endocytosis is dispersible for TGF-beta-mediated activation of Smad2 and that this activation can be mediated by both SARA-dependent and -independent mechanisms.

Activin Receptors, Type I↗
PubMed2002

Regulation of cell proliferation, apoptosis, and carcinogenesis by activin.

The aim of this review is to provide insight into the molecular mechanisms by which activin A modulates cell proliferation, apoptosis, and carcinogenesis in vitro and in vivo. Activin A, a member of the TGFbeta superfamily, has various effects on diverse biological systems, including cell growth inhibition in many cell types. However, the mechanism(s) by which activin exerts its inhibitory effects are not yet understood. This review highlights activin's effects on activin receptors and signaling pathway, modulation of activin signaling, and regulation of cell proliferation and apoptosis by activin. Based on the experiences of all the authors, we emphasized cell cycle inhibitors such as p16 and p21 and regulators of apoptosis such as p53 and members of the bcl-2 family. Aside from activin's inhibition of cell proliferation and enhancement of apoptosis, other newly developed methods for molecular studies of apoptosis by activin were briefly presented that support the role of activin as an inhibitor of carcinogenesis and cancer progression. These methods include subtractive hybridization based on covalent bonding, a simple and accurate means to determine molecular profile of as few as 20 cells based on an RNA-PCR approach, and a messenger RNA-antisense DNA interference phenomenon (D-RNAi), resulting in a long-term gene knockout effects.

Activin Receptors↗