The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform

Shoukat Dedhar - One of the best experts on this subject based on the ideXlab platform.

  • The integrin linked kinase (ILK) induces an invasive phenotype via AP-1 Transcription Factor-dependent upregulation of matrix metalloproteinase 9 (MMP-9)
    Oncogene, 2000
    Co-Authors: Armelle A Troussard, Penny Costello, T Nathan Yoganathan, Shigehiro Kumagai, Calvin D Roskelley, Shoukat Dedhar
    Abstract:

    Overexpression of Integrin Linked Kinase (ILK) in intestinal and mammary epithelial cells results in a highly invasive phenotype, associated with increased levels of expression of the matrix metalloproteinase MMP-9. This increase was at the Transcriptional level as determined by MMP-9 promoter-CAT reporter assays. Mutations in the two AP-1 binding sites within the MMP-9 promoter completely inhibited the reporter activity. We have previously shown that ILK inhibits glycogen synthase kinase-3 (GSK-3) activity. Transient transfection of wild-type GSK-3β in ILK-overexpressing cells decreased MMP-9 promoter activity and AP-1 activity, indicating that ILK can stimulate MMP-9 expression via GSK-3β and AP-1 Transcription Factor. A small molecule inhibitor of the ILK kinase reduced the in vitro invasiveness of ILK-overexpressing cells as well as the invasiveness of several human brain tumor cell lines. Furthermore, both MMP-9 promoter and AP-1 activities were inhibited by the ILK inhibitor. Invasiveness of ILK-overexpressing cells was also reduced by inhibition of MMP-9. These data demonstrate that ILK can induce an invasive phenotype via AP-1-dependent upregulation of MMP-9.

  • cell extracellular matrix interactions stimulate the ap 1 Transcription Factor in an integrin linked kinase and glycogen synthase kinase 3 dependent manner
    Molecular and Cellular Biology, 1999
    Co-Authors: Armelle A Troussard, Shoukat Dedhar, Clara Tan, Nathan T Yoganathan
    Abstract:

    Integrin-mediated interactions of cells with components of the extracellular matrix regulate cell survival, cell proliferation, cell differentiation, and cell migration. Some of these physiological responses are regulated via activation of Transcription Factors such as activator protein 1 (AP-1). Integrin-linked kinase (ILK) is an ankyrin repeat containing serine-threonine protein kinase whose activity is rapidly and transiently stimulated by cell-fibronectin interactions as well as by insulin stimulation. ILK activates protein kinase B and inhibits the glycogen synthase kinase 3 (GSK-3) activity in a phosphatidylinositol-3-kinase (PI 3-kinase)-dependent manner. We now show that cell adhesion to fibronectin results in a rapid and transient stimulation of AP-1 activity. At the same time, the kinase activity of ILK is stimulated whereas that of GSK-3 is inhibited. This fibronectin-dependent activation of AP-1 activity is inhibited in a dose-dependent manner if the cells are transfected with wild-type GSK-3, and also by inhibitors of PI 3-kinase. Stable or transient overexpression of ILK results in a stimulation of AP-1 activity which is inhibited by cotransfection with wild-type GSK-3 and kinase-deficient ILK. Transient transfection of ILK in HEK-293 cells stimulates complex formation between an AP-1 consensus oligonucleotide and nuclear proteins containing c-jun. The formation of this complex is inhibited by cotransfection with active GSK-3 or kinase-deficient ILK, suggesting that ILK may regulate AP-1 activation by inhibiting GSK-3, which has previously been shown to be a negative regulator of AP-1. In the presence of serum, ILK has no effect on the phosphorylation of Ser-73 in the N-terminal transactivation domain of c-jun. These results demonstrate a novel signaling pathway for the adhesion-mediated stimulation of AP-1 Transcriptional activity involving ILK and GSK-3 and the subsequent regulation of the c-jun–DNA interaction.

Soh Yamazaki - One of the best experts on this subject based on the ideXlab platform.

  • regulation of t cell differentiation by the ap 1 Transcription Factor junb
    Immunological medicine, 2021
    Co-Authors: Takaharu Katagiri, Hideto Kameda, Hiroyasu Nakano, Soh Yamazaki
    Abstract:

    JunB, a component of the activator protein-1 (AP-1) Transcription Factor, is known to exhibit an important role in bone formation and bone marrow cell proliferation. During T helper type 2 (Th2) cell differentiation, JunB contributes to the regulation of interleukin (IL)-4 expression, and AP-1 and nuclear Factor of activated T cell (NFAT) constitute a heteromer and contribute to IL-2 production. However, the role of JunB in other T cells has not been investigated. In 2017, it was revealed that JunB, in collaboration with basic leucine zipper ATF-like Transcription Factor (BATF), regulates the expression of Th17-related genes. Furthermore, JunB was found to play an important role in regulatory T (Treg) cell differentiation, contributing to CD25 expression and IL-2 production. IL-2 is a T cell activator and has been shown as a necessary Factor for Treg proliferation. Here, we review the role of JunB in T cells based on basic research data and discuss the potential for its clinical applications.

  • JunB plays a crucial role in development of regulatory T cells by promoting IL-2 signaling
    Mucosal Immunology, 2019
    Co-Authors: Takaharu Katagiri, Soh Yamazaki, Yuto Fukui, Kotaro Aoki, Hideo Yagita, Takashi Nishina, Tetuo Mikami, Sayaka Katagiri, Ayako Shiraishi, Soichiro Kimura
    Abstract:

    The AP-1 Transcription Factor JunB plays crucial roles in multiple biological processes, including placental formation and bone homeostasis. We recently reported that JunB is essential for development of Th17 cells, and thus Junb -deficient mice are resistant to experimental autoimmune encephalomyelitis. However, the role of JunB in CD4^+ T cells under other inflammatory disease conditions is unknown. Here we show that mice lacking JunB in CD4^+ T cells ( Junb ^fl/fl Cd4-Cre mice) were more susceptible to dextran sulfate sodium (DSS)-induced colitis because of impaired development of regulatory T (Treg) cells. Production of interleukin (IL)-2 and expression of CD25, a high affinity IL-2 receptor component, were decreased in Junb -deficient CD4^+ T cells in vitro and in vivo. Naive CD4^+ T cells from Junb ^fl/fl Cd4-Cre mice failed to differentiate into Treg cells in the absence of exogenously added IL-2 in vitro. A mixed bone marrow transfer experiment revealed that defective Treg development of Junb -deficient CD4^+ T cells was not rescued by co-transferred wild-type cells, indicating a significance of the cell-intrinsic defect. Injection of IL-2-anti-IL-2 antibody complexes induced expansion of Treg cells and alleviated DSS-induced colitis in Junb ^fl/fl Cd4-Cre mice. Thus JunB plays a crucial role in the development of Treg cells by facilitating IL-2 signaling.

  • The AP-1 Transcription Factor JunB is required for Th17 cell differentiation
    Scientific reports, 2017
    Co-Authors: Soh Yamazaki, Takaharu Katagiri, Yoshihiko Tanaka, Hiromitsu Araki, Akira Kohda, Fumiyuki Sanematsu, Tomoko Arasaki, Xuefeng Duan, Fumihito Miura, Ryodai Shindo
    Abstract:

    Interleukin (IL)-17-producing T helper (Th17) cells are crucial for host defense against extracellular microbes and pathogenesis of autoimmune diseases. Here we show that the AP-1 Transcription Factor JunB is required for Th17 cell development. Junb-deficient CD4+ T cells are able to develop in vitro into various helper T subsets except Th17. The RNA-seq transcriptome analysis reveals that JunB is crucial for the Th17-specific gene expression program. Junb-deficient mice are completely resistant to experimental autoimmune encephalomyelitis, a Th17-mediated inflammatory disease, and naive T helper cells from such mice fail to differentiate into Th17 cells. JunB appears to activate Th17 signature genes by forming a heterodimer with BATF, another AP-1 Factor essential for Th17 differentiation. The mechanism whereby JunB controls Th17 cell development likely involves activation of the genes for the Th17 lineage-specifying orphan receptors RORγt and RORα and reduced expression of Foxp3, a Transcription Factor known to antagonize RORγt function.

Takaharu Katagiri - One of the best experts on this subject based on the ideXlab platform.

  • regulation of t cell differentiation by the ap 1 Transcription Factor junb
    Immunological medicine, 2021
    Co-Authors: Takaharu Katagiri, Hideto Kameda, Hiroyasu Nakano, Soh Yamazaki
    Abstract:

    JunB, a component of the activator protein-1 (AP-1) Transcription Factor, is known to exhibit an important role in bone formation and bone marrow cell proliferation. During T helper type 2 (Th2) cell differentiation, JunB contributes to the regulation of interleukin (IL)-4 expression, and AP-1 and nuclear Factor of activated T cell (NFAT) constitute a heteromer and contribute to IL-2 production. However, the role of JunB in other T cells has not been investigated. In 2017, it was revealed that JunB, in collaboration with basic leucine zipper ATF-like Transcription Factor (BATF), regulates the expression of Th17-related genes. Furthermore, JunB was found to play an important role in regulatory T (Treg) cell differentiation, contributing to CD25 expression and IL-2 production. IL-2 is a T cell activator and has been shown as a necessary Factor for Treg proliferation. Here, we review the role of JunB in T cells based on basic research data and discuss the potential for its clinical applications.

  • JunB plays a crucial role in development of regulatory T cells by promoting IL-2 signaling
    Mucosal Immunology, 2019
    Co-Authors: Takaharu Katagiri, Soh Yamazaki, Yuto Fukui, Kotaro Aoki, Hideo Yagita, Takashi Nishina, Tetuo Mikami, Sayaka Katagiri, Ayako Shiraishi, Soichiro Kimura
    Abstract:

    The AP-1 Transcription Factor JunB plays crucial roles in multiple biological processes, including placental formation and bone homeostasis. We recently reported that JunB is essential for development of Th17 cells, and thus Junb -deficient mice are resistant to experimental autoimmune encephalomyelitis. However, the role of JunB in CD4^+ T cells under other inflammatory disease conditions is unknown. Here we show that mice lacking JunB in CD4^+ T cells ( Junb ^fl/fl Cd4-Cre mice) were more susceptible to dextran sulfate sodium (DSS)-induced colitis because of impaired development of regulatory T (Treg) cells. Production of interleukin (IL)-2 and expression of CD25, a high affinity IL-2 receptor component, were decreased in Junb -deficient CD4^+ T cells in vitro and in vivo. Naive CD4^+ T cells from Junb ^fl/fl Cd4-Cre mice failed to differentiate into Treg cells in the absence of exogenously added IL-2 in vitro. A mixed bone marrow transfer experiment revealed that defective Treg development of Junb -deficient CD4^+ T cells was not rescued by co-transferred wild-type cells, indicating a significance of the cell-intrinsic defect. Injection of IL-2-anti-IL-2 antibody complexes induced expansion of Treg cells and alleviated DSS-induced colitis in Junb ^fl/fl Cd4-Cre mice. Thus JunB plays a crucial role in the development of Treg cells by facilitating IL-2 signaling.

  • The AP-1 Transcription Factor JunB is required for Th17 cell differentiation
    Scientific reports, 2017
    Co-Authors: Soh Yamazaki, Takaharu Katagiri, Yoshihiko Tanaka, Hiromitsu Araki, Akira Kohda, Fumiyuki Sanematsu, Tomoko Arasaki, Xuefeng Duan, Fumihito Miura, Ryodai Shindo
    Abstract:

    Interleukin (IL)-17-producing T helper (Th17) cells are crucial for host defense against extracellular microbes and pathogenesis of autoimmune diseases. Here we show that the AP-1 Transcription Factor JunB is required for Th17 cell development. Junb-deficient CD4+ T cells are able to develop in vitro into various helper T subsets except Th17. The RNA-seq transcriptome analysis reveals that JunB is crucial for the Th17-specific gene expression program. Junb-deficient mice are completely resistant to experimental autoimmune encephalomyelitis, a Th17-mediated inflammatory disease, and naive T helper cells from such mice fail to differentiate into Th17 cells. JunB appears to activate Th17 signature genes by forming a heterodimer with BATF, another AP-1 Factor essential for Th17 differentiation. The mechanism whereby JunB controls Th17 cell development likely involves activation of the genes for the Th17 lineage-specifying orphan receptors RORγt and RORα and reduced expression of Foxp3, a Transcription Factor known to antagonize RORγt function.

Erwin F. Wagner - One of the best experts on this subject based on the ideXlab platform.

  • liver carcinogenesis by fos dependent inflammation and cholesterol dysregulation
    Journal of Experimental Medicine, 2017
    Co-Authors: Latifa Bakiri, Rainer Hamacher, Osvaldo Grana, Ana Guiocarrion, Ramon Camposolivas, Lola Martinez, Hans Peter Dienes, Martin K Thomsen, Sebastian C Hasenfuss, Erwin F. Wagner
    Abstract:

    Human hepatocellular carcinomas (HCCs), which arise on a background of chronic liver damage and inflammation, express c-Fos, a component of the AP-1 Transcription Factor. Using mouse models, we show that hepatocyte-specific deletion of c-Fos protects against diethylnitrosamine (DEN)-induced HCCs, whereas liver-specific c-Fos expression leads to reversible premalignant hepatocyte transformation and enhanced DEN-carcinogenesis. c-Fos–expressing livers display necrotic foci, immune cell infiltration, and altered hepatocyte morphology. Furthermore, increased proliferation, dedifferentiation, activation of the DNA damage response, and gene signatures of aggressive HCCs are observed. Mechanistically, c-Fos decreases expression and activity of the nuclear receptor LXRα, leading to increased hepatic cholesterol and accumulation of toxic oxysterols and bile acids. The phenotypic consequences of c-Fos expression are partially ameliorated by the anti-inflammatory drug sulindac and largely prevented by statin treatment. An inverse correlation between c-FOS and the LXRα pathway was also observed in human HCC cell lines and datasets. These findings provide a novel link between chronic inflammation and metabolic pathways important in liver cancer.

  • Osteogenic capillaries orchestrate growth plate-independent ossification of the malleus
    Development (Cambridge England), 2015
    Co-Authors: Koichi Matsuo, Erwin F. Wagner, Latifa Bakiri, Yukiko Kuroda, Nobuhito Nango, Kouji Shimoda, Yoshiaki Kubota, Masatsugu Ema, Yoshihiro Takeda, Wataru Yashiro
    Abstract:

    Endochondral ossification is a developmental process by which cartilage is replaced by bone. Terminally differentiated hypertrophic chondrocytes are calcified, vascularized, and removed by chondroclasts before bone matrix is laid down by osteoblasts. In mammals, the malleus is one of three auditory ossicles that transmit vibrations of the tympanic membrane to the inner ear. The malleus is formed from a cartilaginous precursor without growth plate involvement, but little is known about how bones of this type undergo endochondral ossification. Here, we demonstrate that in the processus brevis of the malleus, clusters of osteoblasts surrounding the capillary loop produce bone matrix, causing the volume of the capillary lumen to decrease rapidly in post-weaning mice. Synchrotron X-ray tomographic microscopy revealed a concentric, cylindrical arrangement of osteocyte lacunae along capillaries, indicative of pericapillary bone formation. Moreover, we report that overexpression of Fosl1, which encodes a component of the AP-1 Transcription Factor complex, in osteoblasts significantly blocked malleal capillary narrowing. These data suggest that osteoblast/endothelial cell interactions control growth plate-free endochondral ossification through 'osteogenic capillaries' in a Fosl1-regulated manner.

  • the ap 1 Transcription Factor junb promotes multiple myeloma mm cell proliferation survival and drug resistance in the bone marrow microenvironment
    Blood, 2014
    Co-Authors: Fengjuan Fan, Erwin F. Wagner, Latifa Bakiri, Sonia Vallet, Martin Sattler, Giovanni Tonon, Muhammad Hasan Bashari, Hartmut Goldschmidt, Dirk Jaeger, Klaus Podar
    Abstract:

    MEK/ERK and NF-kB signaling pathways have been reported to play a key role in multiple myeloma (MM) survival, proliferation and drug resistance. These pathways regulate the activity of numerous Transcription Factors. For example, the activator protein-1 (AP-1) Transcription Factor has been implicated in a multitude of physiologic processes, but also tumorigenesis. However, the function of AP-1 in MM is largely unknown. Our data show a vast variety of AP-1 (c-Jun, JunB, JunD, c-Maf and c-Fos) expression levels in MM cells. Importantly, co-culture of MM cells with bone marrow stromal cells (BMSCs), i.e. isotypic primary BMSCs as well as BMSC lines KM-105 and HS-27A, rapidly and strongly induces expression of JunB, but not other AP-1 members. Previous studies have shown that JunB exerts opposite functions depending on the cellular origin and the physiopathological context. For example, it serves as a gatekeeper in acute and chronic myeloid leukemia, but as a positive regulator in Hodgkin9s lymphomas and anaplastic large cell lymphomas. The relevance of JunB activity in MM growth, survival and drug resistance is elusive. First, our data demonstrate that induction of JunB is predominantly mediated by soluble Factors secreted by BMSCs rather than direct MM-BMSC contact. Indeed, using cytokine arrays, we identified IL-6 among the most potent Factors that trigger JunB expression. Mechanistically, JunB upregulation occurs at both Transcriptional as well as translational level. Pharmacologic inhibition was used next in order to identify upstream signaling pathways, which mediate BMSC- induced JunB upregulation in MM cells. Our data show that activation of MEK/ERK or NF-kB is required for induction of JunB expression and AP-1 Transcriptional activity. To delineate the specific functional role of JunB in MM pathogenesis, we transduced MM cells with pLKO.1-JunB shRNA or pLKO.1-scrambled shRNA (SCR). After puromycin- selection, effects of JunB knockdown on MM proliferation, survival and drug resistance were analyzed by 3H-thymidine incorporation, flow cytometry and western blot. Indeed, we observed significant inhibition of proliferation in MM/ JunB shRNA (decreased to ~ 25 – 40 %, p Furthermore, 4-hydroxytamoxifen (4-OHT) treatment of MM cell lines stably transduced with pMSCV-JunB-ER-IRES-GFP but not pMSCV-IRES-GFP induced significant AP-1 luciferase activity (~ 3.3 fold, p 1000 MM patient samples of different prognostic groups were compared to samples from healthy donors using the gene set enrichment analysis (GSEA). Our results further support a key role for JunB in MM pathogenesis. In summary, our data demonstrate for the first time an important role of JunB/AP-1 in MM tumorigenesis and strongly propose it as a novel therapeutic target in MM. Disclosures No relevant conflicts of interest to declare.

  • junb deficiency leads to a myeloproliferative disorder arising from hematopoietic stem cells
    Cell, 2004
    Co-Authors: Emmanuelle Passegue, Erwin F. Wagner, Irving L Weissman
    Abstract:

    The AP-1 Transcription Factor JunB is a Transcriptional regulator of myelopoiesis. Inactivation of JunB in postnatal mice results in a myeloproliferative disorder (MPD) resembling early human chronic myelogenous leukemia (CML). Here, we show that JunB regulates the numbers of hematopoietic stem cells (HSC). JunB overexpression decreases the frequency of long-term HSC (LT-HSC), while JunB inactivation specifically expands the numbers of LT-HSC and granulocyte/macrophage progenitors (GMP) resulting in chronic MPD. Further, we demonstrate that junB inactivation must take place in LT-HSC, and not at later stages of myelopoiesis, to induce MPD and that only junB-deficient LT-HSC are capable of transplanting the MPD to recipient mice. These results demonstrate a stem cell-specific role for JunB in normal and leukemic hematopoiesis and provide experimental evidence that leukemic stem cells (LSC) can reside at the LT-HSC stage of development in a mouse model of MPD.

Gordon Langsley - One of the best experts on this subject based on the ideXlab platform.

  • the secreted theileria annulata ta9 protein contributes to activation of the ap 1 Transcription Factor
    PLOS ONE, 2018
    Co-Authors: Ahmet Hakan Unlu, Shahin Tajeri, Huseyin Bilgin Bilgic, Hasan Eren, Tulin Karagenc, Gordon Langsley
    Abstract:

    Theileria annulata is an obligate intracellular protozoan parasite of the phylum Apicomplexa. Theileria sporozoites invade bovine leukocytes and develop into a multinucleate syncytial macroschizont that causes uncontrolled proliferation and dissemination of infected and transformed leukocytes. Activator protein 1 (AP-1) is a Transcription Factor driving expression of genes involved in proliferation and dissemination and is therefore a key player in Theileria-induced leukocytes transformation. Ta9 possesses a signal peptide allowing it to be secreted into the infected leukocyte cytosol and be presented to CD8 T cells in the context of MHC class I. First, we confirmed that Ta9 is secreted into the infected leukocyte cytosol, and then we generated truncated versions of GFP-tagged Ta9 and tested their ability to activate AP-1 in non-infected HEK293T human kidney embryo cells. The ability to activate AP-1-driven Transcription was found to reside in the C-terminal 100 amino acids of Ta9 distant to the N-terminally located epitopes recognised by CD8+ T cells. Secreted Ta9 has therefore, not only the ability to stimulate CD8+ T cells, but also the potential to activate AP-1-driven Transcription and contribute to T. annulata-induced leukocyte transformation.

  • a tumour necrosis Factor alpha autocrine loop contributes to proliferation and nuclear Factor kappab activation of theileria parva transformed b cells
    Cellular Microbiology, 2003
    Co-Authors: Julien Guergnon, Marie Chaussepied, P Sopp, Regina Lizundia, Mariefrancoise Moreau, Brigitte Blumen, Dirk Werling, C J Howard, Gordon Langsley
    Abstract:

    Summary Theileria infection of bovine leucocytes induces uncontrolled proliferation and a transformed pheno- type comparable to tumour cells. Infected cells have many characteristics of activated leucocytes and use autocrine loops to augment proliferation. We have shown previously that, in infected B cells, PI3-K con- trols a granulocyte-macrophage colony-stimulating Factor (GM-CSF) autocrine loop to increase both pro- liferation and activation of the activator protein 1 (AP-1) Transcription Factor. We show here that the same infected B cells also use a tumour necrosis Factor (TNF) alpha autocrine loop that again contrib- utes to proliferation and augments nuclear Factor (NF)- k B activation. Interestingly, both pharmacologi- cal inhibition of TNF synthesis and neutralizing anti- TNF antibodies lead to a reduction in proliferation and a 50% drop in NF- k k k B activation, without inducing