Publications (39)133.11 Total impact
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Article: Catecholamine-Induced β2-Adrenergic Receptor Activation Mediates Desensitization of Gastric Cancer Cells to Trastuzumab by Upregulating MUC4 Expression.
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ABSTRACT: Trastuzumab is currently used for patients with Her2(+) advanced gastric cancer. However, the response rate to trastuzumab among the patients is low. The molecular mechanisms underlying trastuzumab resistance in gastric cancer are unknown. Our in vitro data show that activation of β2-adrenergic receptor (β2-AR) triggered by catecholamine caused "targeting failure" of trastuzumab in gastric cancer cells. The antitumor activities of trastuzumab were significantly impeded by chronic catecholamine stimulation in gastric cancer cells and in the mice bearing human gastric cancer xenografts. Mechanistically, catecholamine induced upregulation of the MUC4 expression at both transcription and protein levels via activating STAT3 and ERK. The effects of catecholamine could be effectively blocked by β2-AR antagonist ICI-118,551, indicating that β2-AR-mediated signaling pathway plays a key role in upregulation of MUC4, which was previously demonstrated to interfere with the recognition and physical binding of trastuzumab to Her2 molecules. Moreover, a significant elevation of the MUC4 level was observed in the xenograft tissues in nude mice chronically treated with isoproterenol. Knockdown of MUC4 restored the binding activities of trastuzumab to Her2-overexpressing gastric cancer cells. In addition, coexpression of β2-AR and MUC4 were observed in gastric cancer tissues. Our data indicated a novel trastuzumab resistance mechanism, by which catecholamine-induced β2-AR activation mediates desensitization of gastric cancer cells to trastuzumab through upregulating the MUC4 expression.The Journal of Immunology 04/2013; · 5.79 Impact Factor -
Article: Ribosomal protein S7 regulates arsenite-induced GADD45α expression by attenuating MDM2-mediated GADD45α ubiquitination and degradation.
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ABSTRACT: The stress-responding protein, GADD45α, plays important roles in cell cycle checkpoint, DNA repair and apoptosis. In our recent study, we demonstrate that GADD45α undergoes a dynamic ubiquitination and degradation in vivo, which process can be blocked by the cytotoxic reagent, arsenite, resulting in GADD45α accumulation to activate JNKs cell death pathway, thereby revealing a novel mechanism for the cellular GADD45α functional regulation. But the factors involved in GADD45α stability modulations are unidentified. Here, we demonstrated that MDM2 was an E3 ubiquitin ligase for GADD45α. One of MDM2-binding partner, ribosomal protein S7, interacted with and stabilized GADD45α through preventing the ubiquitination and degradation of GADD45α mediated by MDM2. This novel function of S7 is unrelated to p53 but seems to depend on S7/MDM2 interaction, for the S7 mutant lacking MDM2-binding ability lost its function to stabilize GADD45α. Further investigations indicated that arsenite treatment enhanced S7-MDM2 interaction, resulting in attenuation of MDM2-dependent GADD45α ubiquitination and degradation, thereby leading to GADD45α-dependent cell death pathway activation. Silencing S7 expression suppressed GADD45α-dependent cytotoxicity induced by arsenite. Our findings thus identify a novel function of S7 in control of GADD45α stabilization under both basal and stress conditions and its significance in mediating arsenite-induced cellular stress.Nucleic Acids Research 04/2013; · 8.03 Impact Factor -
Article: p85α mediates NFAT3-dependent VEGF induction in the cellular UVB response.
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ABSTRACT: Exposure to solar ultraviolet B (UVB) radiation is known to induce multiple pathological reactions in the skin. In these processes, up-regulation of VEGF expression has been demonstrated to be important for mediating the angiogenesis-associated photodamage and even skin cancers. However, the signaling events that are responsible for VEGF induction under UVB exposure have not been fully defined. Here, we demonstrate that the regulatory subunit of the PI-3K, p85α, plays a novel role in mediating UVB-induced VEGF expression in the mouse embryonic fibroblasts (MEFs) and the mouse epithermal cells, which effect is unrelated to the PI-3K activity. The transcriptional factor NFAT3 functions as a downstream target of p85α to mediate the induction of VEGF expression in the UVB response. Although lacking NFAT3-binding ability, p85α is required for the recruitment of NFAT3 to the NFAT-responsive element within the vegf promoter. Furthermore, by identifying the adjacent NFAT- and AP-1-binding sites within the vegf promoter, we also find a induced interaction between NFAT3 and one of the AP-1 components, c-Fos, after UVB irradiation. Without the aid of c-Fos, NFAT3 lost its vegf promoter-binding ability. Taken together, our results have revealed a novel PI-3K-independent role for p85α in controlling VEGF induction during the cellular UVB response by regulating NFAT3 activity. Targeting p85α might be helpful for preventing the UVB-induced angiogenesis and the associated photodamage.Journal of Cell Science 02/2013; · 6.11 Impact Factor -
Article: β2-AR-induced Her2 transactivation mediated by Erbin confers protection from apoptosis in cardiomyocytes.
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ABSTRACT: BACKGROUND: Her2 and β2-adrenergic receptor (β2-AR) can form a heterocomplex in cardiomyocytes and agonists can induce Her2 transactivation, which is important for cardiovascular homeostasis. The scaffolding molecules that mediate β2-AR/Her2 interaction are currently unknown. Erbin, a PDZ domain-containing protein is a binding partner of Her2. The C-terminus of β2-AR harbors a PDZ domain-binding motif. Hypothesis of this study is that Erbin may organize the assembly of β2-AR/Her2 complex. METHODS: The interaction among β2-AR, Her2 and Erbin was investigated in COS-7, HEK-293 and H9c2 cells and rat brain and heart tissues by coimmunoprecipitation. The β2-AR binding region of Erbin was identified by utilizing the Erbin deletion mutants. The functional significance of Erbin in cardiomyocytes was determined by Erbin silencing, contraction frequency measurement and cellular apoptosis assays. RESULTS: Erbin was able to form a complex with both exogenous and endogenous β2-AR and Her2 in the presence of isoproterenol (ISO). Deletion of the Erbin LRR domain did not affect its binding to β2-AR and Her2, whereas lacking of the PDZ domain lost the ability of Erbin. Silencing of Erbin greatly abrogated ISO-induced activation of ERK. The treatment of H9c2 cells transfected with the Erbin siRNA with ISO caused severe cell apoptosis. Knock-down of Erbin expression in primary neonatal rat cardiomyocytes led to a remarkable reduction of the beating frequency after ISO stimulation. CONCLUSIONS: Erbin mediates catecholamine-induced β2-AR/Her2 complexation and promotes catecholamine-induced activation of ERK signaling in cardiomyocytes, conferring protection of cardiomyocytes from apoptosis induced by chronic catecholamine stimulation.International journal of cardiology 05/2012; · 7.08 Impact Factor -
Article: cDNA cloning and function analysis of two novel erythroid differentiation related genes
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ABSTRACT: Our previous studies showed that some nuclear proteins that were expressed especially during terminal differentiation of erythroid cells might interact directly or indirectly with HS2 sequence to form the HS2-protein complexes and thus play an important role in the globin gene regulation and erythroid differentiation. Monoclonal antibodies against the nuclear proteins of terminal differentiated erythroid cells, including intermediate and late erythroblasts of human fetal liver and hemin induced K562 cells, were prepared by hybridoma technique. The monoclonal antibodies were used to screen λ-gtll human cDNA expression library of fetal liver in order to obtain the relevant cDNA clones. By the analysis of their cDNA clones and the identification of the proteins’ functions, the regulation mechanism of the HS2 binding proteins might be better understood. Two cDNA clones (GenBank accession number AF040247 and AF040248 respectively) were obtained and one of them owns a full length and the other encodes a protein characterized by a leucine-zipper domain. Both of them were expressed differentially in K562 cells and hemin-induced K562 cells. The evidence suggested that both of them were involved in erythroid differentiation. We investigated the expression pattern ofEDRF1 andEDRF2 by RT-PCR technique. The results of RT-PCR suggested that EDRF1 and EDRF2 might play a critical role in early stage of organ development and histological differentiation. EDRF1 and EDRF2 might start the program of erythroid development, and also regulate the development of erythroid tissue and the expression of globin gene at different stage of the development.Science in China Series C Life Sciences 04/2012; 44(1):99-105. · 1.61 Impact Factor -
Article: Glucocorticoid regulation of a novel HPV-E6-p53-miR-145 pathway modulates invasion and therapy resistance of cervical cancer cells.
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ABSTRACT: Glucocorticoids are stress-responsive neuroendocrine mediators and play an important role in malignant progression, especially in solid tumours. We demonstrate a novel mechanism by which glucocorticoids modulate p53-dependent miR-145 expression in HPV-positive cervical cancer cells through induction of E6 proteins. We found that expression of miR-145 was reduced in cervical cancer tissues. Cortisol induced HPV-E6 expression and suppressed p53 and miR-145 in cervical cancer cells. MiR-145 expression in cervical cancer cells was wild-type p53-dependent, and cortisol-induced down-regulation of miR-145 expression prevented chemotherapy-induced apoptosis, whereas over-expression of miR-145 enhanced sensitivity to mitomycin and reversed the chemoresistance induced by glucocorticoids. We also show that miR-145 augments the effects of p53 by suppressing the inhibitors of p53 in cervical cancer cells, suggesting that miR-145 plays a role in p53 tumour suppression. Finally, we demonstrate that miR-145 inhibits both the motility and invasion of cervical cancer cells. Our findings identify a novel pathway through which the neuroendocrine macroenvironment affects cervical tumour growth, invasion and therapy resistance and show that miR-145 may serve as a target for cervical cancer therapy. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.The Journal of Pathology 01/2012; 228(2):148-57. · 6.32 Impact Factor -
Article: c-Myb regulates cell cycle-dependent expression of Erbin: an implication for a novel function of Erbin.
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ABSTRACT: In the present study, we demonstrated the cell cycle periodicity of Erbin expression with the maximal expression of Erbin in G2/M phase. A significant increase in Erbin promoter activity was observed in G2/M phase-synchronized cells. Sequence analysis revealed a c-Myb site in the core promoter region of Erbin. Mutagenesis of c-Myb consensus sequences abrogated the increased Erbin promoter activity in G2/M phase. ChIP and oligonucleotide pull-down assays validated that the recruitment of c-Myb to the consensus sequences was specific. The interaction of c-Myb with c-Myb site in the Erbin promoter was significantly enhanced in G2/M phase. Ectopic overexpression of c-Myb led to the up-regulation of Erbin promoter activity and c-Myb silencing by small interfering RNA significantly decreased Erbin protein level. Transfection of c-Myb rescued Erbin expression that was impaired by c-Myb knockdown. It proves that c-Myb and the c-Myb response element mediate the cell cycle-dependent expression of Erbin. Inactivation of Erbin causes an acceleration of the G1/S transition, the formation of multipolar spindles and abnormal chromosome congression. These results unravel a critical role of c-Myb in promoting Erbin transcription in G2/M phase and also predict an unappreciated function of Erbin in cell cycle progression.PLoS ONE 01/2012; 7(8):e42903. · 4.09 Impact Factor -
Article: All-Trans-Retinoic Acid Modulates ICAM-1 N-Glycan Composition by Influencing GnT-III Levels and Inhibits Cell Adhesion and Trans-Endothelial Migration.
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ABSTRACT: Changes in the expression of glycosyltransferases directly influence the oligosaccharide structures and conformations of cell surface glycoproteins and consequently cellular phenotype transitions and biological behaviors. In the present study, we show that all-trans-retinoic acid (ATRA) modulates the N-glycan composition of intercellular adhesion molecule-1 (ICAM-1) by manipulating the expression of two N-acetylglucosaminyltransferases, GnT-III and GnT-V, via the ERK signaling pathway. Exposure of various cells to ATRA caused a remarkable gel mobility down-shift of ICAM-1. Treatment with PNGase F confirmed that the reduction of the ICAM-1 molecular mass is attributed to the decreased complexity of N-glycans. We noticed that the expression of the mRNA encoding GnT-III, which stops branching, was significantly enhanced following ATRA exposure. In contrast, the level of the mRNA encoding GnT-V, which promotes branching, was reduced following ATRA exposure. Silencing of GnT-III prevented the molecular mass shift of ICAM-1. Moreover, ATRA induction greatly inhibited the adhesion of SW480 and U937 cells to the HUVEC monolayer, whereas knock-down of GnT-III expression effectively restored cell adhesion function. Treatment with ATRA also dramatically reduced the trans-endothelial migration of U937 cells. These data indicate that the alteration of ICAM-1 N-glycan composition by ATRA-induced GnT-III activities hindered cell adhesion and cell migration functions simultaneously, pinpointing a unique regulatory role of specific glycosyltransferases in the biological behaviors of tumor cells and a novel function of ATRA in the modulation of ICAM-1 N-glycan composition.PLoS ONE 01/2012; 7(12):e52975. · 4.09 Impact Factor -
Article: Modulation of IFN-γ receptor 1 expression by AP-2α influences IFN-γ sensitivity of cancer cells.
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ABSTRACT: Interferon (IFN)-γ plays crucial roles in regulating both innate and adaptive immunity. The existence of IFN-γ receptor 1 (IFNGR1) molecules on the cell surface is a prerequisite to the initiation of IFN-γ signaling; low expression of IFNGR1 leads to a functional blockade of IFN-γ signaling. However, the molecular mechanisms by which IFNGR1 expression is controlled are unclear. In the present study, we demonstrated that IFNGR1 expression was reduced or lost in breast cancer. Heterogeneous IFNGR1 immunoreactivity appeared to be associated with the morphological heterogeneity of breast cancer, and loss of IFNGR1 expression was predominantly observed in poorly differentiated areas. We identified the functional activating protein (AP)-2 and specificity protein (SP)-1 sites within the IFNGR1 promoter. Ectopic expression of AP-2α drastically repressed the expression of IFNGR1 and hindered IFN-γ signaling, whereas AP-2α gene silencing elevated IFNGR1 levels. Overexpression of SP-1 effectively antagonized the repressive effects of AP-2α. Simultaneous recruitment of both transcription factors to the AP-2 and SP-1 motifs, respectively, in the IFNGR1 promoter was demonstrated, implying that AP-2α and SP-1 may synergistically modulate IFNGR1 transcription. Moreover, AP-2α overexpression in AP-2-deficient SW480 cells remarkably inhibited Stat1 phosphorylation and the anti-proliferative effects of IFN-γ, whereas knockdown of the AP-2α expression dramatically enhanced the sensitivities of HeLa cells highly expressing AP-2 to IFN-γ, indicating that dysregulation of AP-2α expression is associated with impaired IFN-γ actions in cancer cells.American Journal Of Pathology 12/2011; 180(2):661-71. · 4.89 Impact Factor -
Article: IKKα contributes to UVB-induced VEGF expression by regulating AP-1 transactivation.
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ABSTRACT: Exposure to ultraviolet B (UVB) irradiation from sunlight induces the upregulation of VEGF, a potent angiogenic factor that is critical for mediating angiogenesis-associated photodamage. However, the molecular mechanisms related to UVB-induced VEGF expression have not been fully defined. Here, we demonstrate that one of the catalytic subunits of the IκB kinase complex (IKK), IKKα, plays a critical role in mediating UVB-induced VEGF expression in mouse embryonic fibroblasts (MEFs), which requires IKKα kinase activity but is independent of IKKβ, IKKγ and the transactivation of NF-κB. We further show that the transcriptional factor AP-1 functions as the downstream target of IKKα that is responsible for VEGF induction under UVB exposure. Both the accumulation of AP-1 component, c-Fos and the transactivation of AP-1 by UVB require the activated IKKα located within the nucleus. Moreover, nuclear IKKα can associate with c-Fos and recruit to the vegf promoter regions containing AP-1-responsive element and then trigger phosphorylation of the promoter-bound histone H3. Thus, our results have revealed a novel independent role for IKKα in controlling VEGF expression during the cellular UVB response by regulating the induction of the AP-1 component and phosphorylating histone H3 to facilitate AP-1 transactivation. Targeting IKKα shows promise for the prevention of UVB-induced angiogenesis and the associated photodamage.Nucleic Acids Research 12/2011; 40(7):2940-55. · 8.03 Impact Factor -
Article: IKKβ downregulation is critical for triggering JNKs-dependent cell apoptotic response in the human hepatoma cells under arsenite exposure.
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ABSTRACT: Arsenite has a long history in treating leukemia, which might be also effective in the therapy of other cancers. Our previous published data have demonstrated that arsenite exposure induces apoptosis in the HepG2 human hepatoma cells via activating JNKs/AP-1 pathway, but the upstream signaling events responsible for JNKs (c-Jun N-terminal kinase) cascade activation have not been fully discovered. Since cross-talk between IKK/NF-κB and JNKs pathways under stress conditions is a hot topic, in this article, we investigate the potential roles of IKKα and IKKβ, the catalytic subunits of IKK complexes, in the arsenite-induced JNKs pathway activation in the HepG2 cells. We found that arsenite exposure induced JNKs and AP-1 activation accompanying with a significant reduction of both IKKα and IKKβ expressions. Overexpression of IKKβ, but not of IKKα, inhibited arsenite-induced MKK7/JNKs/AP-1 pathway activation as well as the apoptotic response. Therefore, we conclude that the downregulation of IKKβ expression is the prerequisite signaling event for mediating JNKs pathway activation and the cellular apoptotic response in the HepG2 cells under arsenite exposure. Targeting IKKβ might be helpful to enhance the tumor therapeutic effect of arsenite.Molecular and Cellular Biochemistry 06/2011; 358(1-2):61-6. · 2.06 Impact Factor -
Article: Catecholamine up-regulates MMP-7 expression by activating AP-1 and STAT3 in gastric cancer.
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ABSTRACT: Stress, anxiety and depression can cause complex physiological and neuroendocrine changes, resulting in increased level of stress related hormone catecholamine, which may constitute a primary mechanism by which physiological factors impact gene expression in tumors. In the present study, we investigated the effects of catecholamine stimulation on MMP-7 expression in gastric cancer cells and elucidated the molecular mechanisms of the up-regulation of MMP-7 level by catecholamine through an adrenergic signaling pathway. Increased MMP-7 expression was identified at both mRNA and protein levels in the gastric cancer cells in response to isoproterenol stimulation. β2-AR antigonist effectively abrogated isoproterenol-induced MMP-7 expression. The activation of STAT3 and AP-1 was prominently induced by isoproterenol stimulation and AP-1 displayed a greater efficacy than STAT3 in isoproterenol-induced MMP-7 expression. Mutagenesis of three STAT3 binding sites in MMP-7 promoter failed to repress the transactivation of MMP-7 promoter and silencing STAT3 expression was not effective in preventing isoproterenol-induced MMP-7 expression. However, isoproterenol-induced MMP-7 promoter activities were completely disappeared when the AP-1 site was mutated. STAT3 and c-Jun could physically interact and bind to the AP-1 site, implicating that the interplay of both transcriptional factors on the AP-1 site is responsible for isoproterenol-stimulated MMP-7 expression in gastric cancer cells. The expression of MMP-7 in gastric cancer tissues was found to be at the site where β2-AR was overexpressed and the levels of MMP-7 and β2-AR were the highest in the metastatic locus of gastric cancer. Up-regulation of MMP-7 expression through β2-AR-mediated signaling pathway is involved in invasion and metastasis of gastric cancer.Molecular Cancer 10/2010; 9:269. · 3.99 Impact Factor -
Article: The β2-adrenergic receptor and Her2 comprise a positive feedback loop in human breast cancer cells.
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ABSTRACT: In this study, β2-AR level was found to be up-regulated in MCF-7 cells overexpressing Her2 (MCF-7/Her2). Correlation of β2-AR level with Her2 status was demonstrated in breast cancer tissue samples. Constitutive phosphorylation of ERK, mRNA expression up-regulation of catecholamine-synthesis enzymes, and increased epinephrine release were detected in MCF-7/Her2 cells. β2-AR expression induced by epinephrine and involvement of ERK signaling were validated. The data indicate that Her2 overexpression and excessive phosphorylation of ERK cause epinephrine autocrine release from breast cancer cells, resulting in up-regulation of β2-AR expression. The data also showed that catecholamine prominently stimulated Her2 mRNA expression and promoter activity. The activation and nuclear translocation of STAT3 triggered by isoproterenol were observed. Enhanced binding activities of STAT3 to the Her2 promoter after isoproterenol stimulation were verified. Using STAT3 shRNA and dominant negative STAT3 mutant, the role of STAT3 in isoproterenol-induced Her2 expression was further confirmed. The data support a model where β2-AR and Her2 comprise a positive feedback loop in human breast cancer cells.Breast Cancer Research and Treatment 03/2010; 125(2):351-62. · 4.43 Impact Factor -
Article: Transactivators Zta and Rta of Epstein-Barr virus promote G0/G1 to S transition in Raji cells: a novel relationship between lytic virus and cell cycle.
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ABSTRACT: In the present study, we show that the treatment of Epstein-Barr virus (EBV) latently infected Raji cells with TPA/SB caused the cell growth arrest. The Zta-positive cells were predominantly enriched in G0/G1 phase of cell cycle. When Zta expression reached a maximal level, a fraction of Zta expressing cell population reentered S phase. Analysis of the expression pattern of a key set of cell cycle regulators revealed that the expression of Zta and Rta substantially interfered with the cell cycle regulatory machinery in Raji cells, strongly inhibiting the expression of Rb and p53 and inducing the expression of E2F1. Down-regulation of Rb was further demonstrated to be mediated by proteasomal degradation, and p53 and p21 affected at transcription level. The data indicate that both Zta and Rta promote entry into S phase of Raji cells. The important roles of Zta and Rta in EBV lytic reactivation were also demonstrated. Our finding suggests that these two transcriptional activators may act synergistically to govern the expression of downstream early and late genes as well as cellular genes and initiation of lytic cycle and manipulation of cell cycle regulatory mechanisms require the joint and interactive contributions of Rta and Zta.Molecular Immunology 03/2010; 47(9):1783-92. · 2.90 Impact Factor -
Article: A novel role of IKKalpha in the mediation of UVB-induced G0/G1 cell cycle arrest response by suppressing Cyclin D1 expression.
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ABSTRACT: Exposure to ultraviolet B (UVB) irradiation (290-320nm wavelength) from sunlight induces a variety of medical problems, including sunburn, immunosuppression and skin cancers. However, the molecular mechanisms related to UVB-induced cell damage and/or mutagenic effects have not been fully defined. Here, we demonstrate that one of the catalytic subunits of the IkappaB kinase complex (IKK), IKKalpha, plays a critical role in mediation of the UVB-induced G0/G1 cell cycle arrest response by suppressing Cyclin D1 expression. Notably, IKKa-dependent Cyclin D1 regulation is unrelated to IKKbeta/NF-kappaB activity. We further show that IKKalpha-dependent downregulation of Cyclin D1 expression in the UVB response results from the reduction of ERK1/2-dependent Cyclin D1 transcription coupled with an increase of p38 kinase-dependent Cyclin D1 proteolysis. Thus, our results have identified the novel role of IKKalpha in regulating cell cycle progression during the cellular UVB response. Targeting IKKalpha might be promising for the prevention of UVB-induced cell damage and tumorigenic effects.Biochimica et Biophysica Acta 02/2010; 1803(2):323-32. · 4.66 Impact Factor -
Article: GADD45alpha mediates arsenite-induced cell apoptotic effect in human hepatoma cells via JNKs/AP-1-dependent pathway.
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ABSTRACT: Arsenite (As(III)), an effective chemotherapeutic agent for the acute promyelocytic leukemia (APL) and multiple myeloma (MM), might be also a promise for the therapy of other cancers, including the solid tumors. However, the molecular bases of arsenite-induced cytotoxicity in the tumor cells have not been fully defined. In this study, we have disclosed that arsenite effectively induces the apoptotic response in the HepG2 human hepatoma cells by triggering GADD45alpha induction and the subsequent activation of JNKs/AP-1 cell death pathway. However, signaling events relating to GADD45alpha/JNKs/AP-1 pathway activation have not been observed in HL7702 human diploid hepatic cells under the same arsenite exposure condition. Our results thus have illustrated the selective pro-apoptotic role of arsenite in the hepatoma cells by activating GADD45alpha-dependent cell death pathway whereas with little effect on the normal hepatic cells. The approaches to up-regulate GADD45alpha levels might be helpful in improving the chemotherapeutic action of arsenite on certain solid tumors including hepatoma.Journal of Cellular Biochemistry 02/2010; 109(6):1264-73. · 2.87 Impact Factor -
Article: Construction and expression of a spliced variant of Epstein-Barr virus bzlf1 and preparation of its polyclonal antibody.
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ABSTRACT: The BZLF1 gene-encoded protein, Zta (EB1, ZEBRA), is a key transcriptional activator of induction of the lytic cycle of EBV. Zta; it contains a basic region with homology to the DNA binding domains of the AP-1 family. In this study, an alternatively spliced BZLF1 (Delta BZLF1) cDNA lacking exon 2, which encodes the DNA-binding domain of Zta, was isolated from B95-8 marmoset cell line releasing EBV. The cDNA was inserted into a prokaryotic expression vector pET-28a+. The His-tagged recombinant protein was overproduced in E. coli BL21(DE3) and purified by nickel affinity chromatography. The purified fraction was characterized by Western blot and MALDI-TOF-MS analysis and used as an antigen to immunize mice. The antibody against Delta Zta can recognize both denatured and natural Zta protein. The Delta Zta protein and its antibody can be used to further investigate its unknown functions.Preparative Biochemistry & Biotechnology 01/2010; 40(1):46-56. · 0.47 Impact Factor -
Article: Down-regulation of MHC class II expression through inhibition of CIITA transcription by lytic transactivator Zta during Epstein-Barr virus reactivation.
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ABSTRACT: The presentation of peptides to T cells by MHC class II molecules is of critical importance in specific recognition to a pathogen by the immune system. The level of MHC class II directly influences T lymphocyte activation. The aim of this study was to identify the possible mechanisms of the down-regulation of MHC class II expression by Zta during EBV lytic cycle. The data in the present study demonstrated that ectopic expression of Zta can strongly inhibit the constitutive expression of MHC class II and CIITA in Raji cells. The negative effect of Zta on the CIITA promoter activity was also observed. Scrutiny of the DNA sequence of CIITA promoter III revealed the presence of two Zta-response element (ZRE) motifs that have complete homology to ZREs in the DR and left-hand side duplicated sequence promoters of EBV. By chromatin immunoprecipitation assays, the binding of Zta to the ZRE(221) in the CIITA promoter was verified. Site-directed mutagenesis of three conserved nucleotides of the ZRE(221) substantially disrupted Zta-mediated inhibition of the CIITA promoter activity. Oligonucleotide pull-down assay showed that mutation of the ZRE(221) dramatically abolished Zta binding. Analysis of the Zta mutant lacking DNA binding domain revealed that the DNA-binding activity of Zta is required for the trans repression of CIITA. The expression of HLA-DRalpha and CIITA was restored by Zta gene silencing. The data indicate that Zta may act as an inhibitor of the MHC class II pathway, suppressing CIITA transcription and thus interfering with the expression of MHC class II molecules.The Journal of Immunology 03/2009; 182(4):1799-809. · 5.79 Impact Factor -
Article: In vitro and in vivo antitumor effect of a trivalent bispecific antibody targeting ErbB2 and CD16.
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ABSTRACT: In order to optimize the structure of bispecific antibody (BsAb) and minimize its toxicity, we developed a trivalent anti-ErbB2/anti-CD16 BsAb. This BsAb possesses three antigen binding sites, two antigen binding sites in the form of scFvs targeting the tumor cells overexpressing ErbB2 and a monovalent Fab fragment redirecting NK cells. Critical for this BsAb is its capacity to trigger cytotoxicity of the effector cells in vitro and in vivo. In the present study, we demonstrated that the BsAb is capable of binding to ErbB2 extracellular domain on SKBR3 cells and effectively direct the cytotoxic activities of effector cells to SKBR3 cells even at a low concentration. The BsAb was more effective to SKBR3 cells than to MCF-7 cells, indicating that the killing of tumor cells was dependent on the density of ErbB2 molecules on cell surface. Furthermore, the BsAb was more potent than anti-ErbB2 single chain antibody (scFv)-Fc fusion proteins in the cytotoxicity assay and in SKOV3 xenograft animals. Improved efficacy demonstrates that the BsAb may be valuable to be further modified and optimized for the treatment of malignant cells in a minimal residual disease.Cancer biology & therapy 12/2008; 7(11):1744-50. · 2.64 Impact Factor -
Article: HER2-dependent MMP-7 expression is mediated by activated STAT3.
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ABSTRACT: MMP-7 expression is highly regulated at the level of transcription. An understanding of how the MMP-7 gene is regulated is critical to elucidate the mechanisms of MMP-7 overexpression in the early tumor development. In the present study, increased mRNA and protein expressions of MMP-7 were observed in MCF-7 cells stably overexpressing HER2 (MCF-7/HER2). The promoter activity of MMP-7 gene was upregulated in MCF-7/HER2 cells and significantly enhanced by HRG induction. Examination of the MMP-7 promoter sequence revealed three potential STAT3 binding sites within the proximal region. MMP-7 promoter activity was remarkably induced in MCF-7 cells expressing the constitutively activated STAT3 (MCF-7/STAT3C). RT-PCR and Western blot analysis confirmed the expression upregulation of mRNA and protein of MMP-7 in the MCF-7/STAT3C cells. Binding of STAT3 to MMP-7 promoter was verified by ChIP and the critical STAT3 element within the MMP-7 promoter identified by the mutagenesis of the core STAT3 recognition sequence. Increased STAT3 phosphorylation was observed in either HER2 overexpressing cells or HRG-induced cells. The data indicate that HRG-induced HER2-dependent transcriptional upregulation and protein secretion of MMP-7 are mediated by activated STAT3. The expression of MMP-7 may be attributed to HER2/STAT3 activation.Cellular Signalling 08/2008; 20(7):1284-91. · 4.06 Impact Factor
Top co-authors
Top Journals
Institutions
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2013
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China Pharmaceutical University
Nanjing, Jiangxi Sheng, China
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2012
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Hebei Medical University
Shijiazhuang, Hebei, China
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2010
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Shandong Academy of Sciences
Jinan, Shandong Sheng, China
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