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  1. Article ; Online: Normal cell cycle progression requires negative regulation of E2F1 by Groucho during S phase and its relief at G2 phase.

    Bar-Cohen, Shaked / Martínez Quiles, María Lorena / Baskin, Alexey / Dawud, Ruba / Jennings, Barbara H / Paroush, Ze'ev

    Development (Cambridge, England)

    2023  Volume 150, Issue 11

    Abstract: The cell cycle depends on a sequence of steps that are triggered and terminated via the synthesis and degradation of phase-specific transcripts and proteins. Although much is known about how stage-specific transcription is activated, less is understood ... ...

    Abstract The cell cycle depends on a sequence of steps that are triggered and terminated via the synthesis and degradation of phase-specific transcripts and proteins. Although much is known about how stage-specific transcription is activated, less is understood about how inappropriate gene expression is suppressed. Here, we demonstrate that Groucho, the Drosophila orthologue of TLE1 and other related human transcriptional corepressors, regulates normal cell cycle progression in vivo. We show that, although Groucho is expressed throughout the cell cycle, its activity is selectively inactivated by phosphorylation, except in S phase when it negatively regulates E2F1. Constitutive Groucho activity, as well as its depletion and the consequent derepression of e2f1, cause cell cycle phenotypes. Our results suggest that Cdk1 contributes to phase-specific phosphorylation of Groucho in vivo. We propose that Groucho and its orthologues play a role in the metazoan cell cycle that may explain the links between TLE corepressors and several types of human cancer.
    MeSH term(s) Animals ; Basic Helix-Loop-Helix Transcription Factors/genetics ; Basic Helix-Loop-Helix Transcription Factors/metabolism ; Cell Cycle/genetics ; Co-Repressor Proteins/genetics ; Co-Repressor Proteins/metabolism ; Drosophila/metabolism ; E2F1 Transcription Factor/genetics ; E2F1 Transcription Factor/metabolism ; G2 Phase ; Repressor Proteins/genetics ; Repressor Proteins/metabolism ; S Phase ; Drosophila Proteins/genetics ; Drosophila Proteins/metabolism
    Chemical Substances Basic Helix-Loop-Helix Transcription Factors ; Co-Repressor Proteins ; E2F1 Transcription Factor ; Repressor Proteins ; E2f1 protein, Drosophila ; gro protein, Drosophila ; Drosophila Proteins
    Language English
    Publishing date 2023-06-01
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 90607-4
    ISSN 1477-9129 ; 0950-1991
    ISSN (online) 1477-9129
    ISSN 0950-1991
    DOI 10.1242/dev.201041
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Ub I Zs.183: Show issues Location:
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  2. Article ; Online: An affinity for brainstem microglia in pediatric high-grade gliomas of brainstem origin.

    Zats, Liat Peretz / Ahmad, Labiba / Casden, Natania / Lee, Meelim J / Belzer, Vitali / Adato, Orit / Bar Cohen, Shaked / Ko, Seung-Hyun B / Filbin, Mariella G / Unger, Ron / Lauffenburger, Douglas A / Segal, Rosalind A / Behar, Oded

    Neuro-oncology advances

    2022  Volume 4, Issue 1, Page(s) vdac117

    Abstract: Background: High-grade gliomas (HGG) in children have a devastating prognosis and occur in a remarkable spatiotemporal pattern. Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPG), typically occur in mid-childhood, while ... ...

    Abstract Background: High-grade gliomas (HGG) in children have a devastating prognosis and occur in a remarkable spatiotemporal pattern. Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPG), typically occur in mid-childhood, while cortical HGGs are more frequent in older children and adults. The mechanisms behind this pattern are not clear.
    Methods: We used mouse organotypic slice cultures and glial cell cultures to test the impact of the microenvironment on human DIPG cells. Comparing the expression between brainstem and cortical microglia identified differentially expressed secreted proteins. The impact of some of these proteins on DIPGs was tested.
    Results: DIPGs, pediatric HGGs of brainstem origin, survive and divide more in organotypic slice cultures originating in the brainstem as compared to the cortex. Moreover, brainstem microglia are better able to support tumors of brainstem origin. A comparison between the two microglial populations revealed differentially expressed genes. One such gene, interleukin-33 (IL33), is highly expressed in the pons of young mice and its DIPG receptor is upregulated in this context. Consistent with this observation, the expression levels of IL33 and its receptor, IL1RL1, are higher in DIPG biopsies compared to low-grade cortical gliomas. Furthermore, IL33 can enhance proliferation and clonability of HGGs of brainstem origin, while blocking IL33 in brainstem organotypic slice cultures reduced the proliferation of these tumor cells.
    Conclusions: Crosstalk between DIPGs and the brainstem microenvironment, in particular microglia, through IL33 and other secreted factors, modulates spatiotemporal patterning of this HGG and could prove to be an important future therapeutic target.
    Language English
    Publishing date 2022-07-21
    Publishing country England
    Document type Journal Article
    ZDB-ID 3009682-0
    ISSN 2632-2498 ; 2632-2498
    ISSN (online) 2632-2498
    ISSN 2632-2498
    DOI 10.1093/noajnl/vdac117
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Novel interplay between JNK and Egfr signaling in Drosophila dorsal closure.

    Kushnir, Tatyana / Mezuman, Sharon / Bar-Cohen, Shaked / Lange, Rotem / Paroush, Ze'ev / Helman, Aharon

    PLoS genetics

    2017  Volume 13, Issue 6, Page(s) e1006860

    Abstract: Dorsal closure (DC) is a developmental process in which two contralateral epithelial sheets migrate to seal a large hole in the dorsal ectoderm of the Drosophila embryo. Two signaling pathways act sequentially to orchestrate this dynamic morphogenetic ... ...

    Abstract Dorsal closure (DC) is a developmental process in which two contralateral epithelial sheets migrate to seal a large hole in the dorsal ectoderm of the Drosophila embryo. Two signaling pathways act sequentially to orchestrate this dynamic morphogenetic process. First, c-Jun N-terminal kinase (JNK) signaling activity in the dorsal-most leading edge (LE) cells of the epidermis induces expression of decapentaplegic (dpp). Second, Dpp, a secreted TGF-β homolog, triggers cell shape changes in the adjacent, ventrally located lateral epidermis, that guide the morphogenetic movements and cell migration mandatory for DC. Here we uncover a cell non-autonomous requirement for the Epidermal growth factor receptor (Egfr) pathway in the lateral epidermis for sustained dpp expression in the LE. Specifically, we demonstrate that Egfr pathway activity in the lateral epidermis prevents expression of the gene scarface (scaf), encoding a secreted antagonist of JNK signaling. In embryos with compromised Egfr signaling, upregulated Scaf causes reduction of JNK activity in LE cells, thereby impeding completion of DC. Our results identify a new developmental role for Egfr signaling in regulating epithelial plasticity via crosstalk with the JNK pathway.
    MeSH term(s) Animals ; Drosophila Proteins/biosynthesis ; Drosophila Proteins/genetics ; Drosophila melanogaster/genetics ; Drosophila melanogaster/growth & development ; Ectoderm/growth & development ; Ectoderm/metabolism ; Embryo, Nonmammalian ; Embryonic Development/genetics ; Epidermis/growth & development ; Epidermis/metabolism ; ErbB Receptors/biosynthesis ; ErbB Receptors/genetics ; Gene Expression Regulation, Developmental ; JNK Mitogen-Activated Protein Kinases/biosynthesis ; JNK Mitogen-Activated Protein Kinases/genetics ; Morphogenesis/genetics ; Receptors, Invertebrate Peptide/biosynthesis ; Receptors, Invertebrate Peptide/genetics ; Serine Proteases/biosynthesis ; Serine Proteases/genetics ; Signal Transduction
    Chemical Substances Drosophila Proteins ; Receptors, Invertebrate Peptide ; dpp protein, Drosophila ; Egfr protein, Drosophila (EC 2.7.10.1) ; ErbB Receptors (EC 2.7.10.1) ; JNK Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; Serine Proteases (EC 3.4.-) ; scaf protein, Drosophila (EC 3.4.-)
    Language English
    Publishing date 2017-06-19
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2186725-2
    ISSN 1553-7404 ; 1553-7390
    ISSN (online) 1553-7404
    ISSN 1553-7390
    DOI 10.1371/journal.pgen.1006860
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: (with research data) Phosphorylated Groucho delays differentiation in the follicle stem cell lineage by providing a molecular memory of EGFR signaling in the niche.

    Johnston, Michael J / Bar-Cohen, Shaked / Paroush, Ze'ev / Nystul, Todd G

    Development (Cambridge, England)

    2016  Volume 143, Issue 24, Page(s) 4631–4642

    Abstract: In the epithelial follicle stem cells (FSCs) of the Drosophila ovary, Epidermal Growth Factor Receptor (EGFR) signaling promotes self-renewal, whereas Notch signaling promotes differentiation of the prefollicle cell (pFC) daughters. We have identified ... ...

    Abstract In the epithelial follicle stem cells (FSCs) of the Drosophila ovary, Epidermal Growth Factor Receptor (EGFR) signaling promotes self-renewal, whereas Notch signaling promotes differentiation of the prefollicle cell (pFC) daughters. We have identified two proteins, Six4 and Groucho (Gro), that link the activity of these two pathways to regulate the earliest cell fate decision in the FSC lineage. Our data indicate that Six4 and Gro promote differentiation towards the polar cell fate by promoting Notch pathway activity. This activity of Gro is antagonized by EGFR signaling, which inhibits Gro-dependent repression via p-ERK mediated phosphorylation. We have found that the phosphorylated form of Gro persists in newly formed pFCs, which may delay differentiation and provide these cells with a temporary memory of the EGFR signal. Collectively, these findings demonstrate that phosphorylated Gro labels a transition state in the FSC lineage and describe the interplay between Notch and EGFR signaling that governs the differentiation processes during this period.
    MeSH term(s) Animals ; Basic Helix-Loop-Helix Transcription Factors/genetics ; Cell Differentiation/genetics ; Drosophila Proteins/genetics ; Drosophila Proteins/metabolism ; Drosophila melanogaster/embryology ; Epithelial Cells/cytology ; ErbB Receptors/metabolism ; Female ; Homeodomain Proteins/genetics ; Homeodomain Proteins/metabolism ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/metabolism ; Ovarian Follicle/cytology ; Ovarian Follicle/embryology ; Phosphorylation ; RNA Interference ; RNA, Small Interfering/genetics ; Receptors, Invertebrate Peptide/metabolism ; Receptors, Notch/metabolism ; Repressor Proteins/genetics ; Signal Transduction/genetics ; Stem Cells/cytology ; Transcription Factors/genetics ; Transcription Factors/metabolism
    Chemical Substances Basic Helix-Loop-Helix Transcription Factors ; Drosophila Proteins ; Homeodomain Proteins ; N protein, Drosophila ; Nerve Tissue Proteins ; RNA, Small Interfering ; Receptors, Invertebrate Peptide ; Receptors, Notch ; Repressor Proteins ; Six4 protein, Drosophila ; Transcription Factors ; gro protein, Drosophila ; Egfr protein, Drosophila (EC 2.7.10.1) ; ErbB Receptors (EC 2.7.10.1)
    Language English
    Publishing date 2016-11-11
    Publishing country England
    Document type Journal Article
    ZDB-ID 90607-4
    ISSN 1477-9129 ; 0950-1991
    ISSN (online) 1477-9129
    ISSN 0950-1991
    DOI 10.1242/dev.143263
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Ub I Zs.183: Show issues Location:
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  5. Article ; Online: An Activating Mutation in ERK Causes Hyperplastic Tumors in a

    Kushnir, Tatyana / Bar-Cohen, Shaked / Mooshayef, Navit / Lange, Rotem / Bar-Sinai, Allan / Rozen, Helit / Salzberg, Adi / Engelberg, David / Paroush, Ze'ev

    Genetics

    2019  Volume 214, Issue 1, Page(s) 109–120

    Abstract: Receptor tyrosine kinase signaling plays prominent roles in tumorigenesis, and activating oncogenic point mutations in the core pathway components Ras, Raf, or MEK are prevalent in many types of cancer. Intriguingly, however, analogous oncogenic ... ...

    Abstract Receptor tyrosine kinase signaling plays prominent roles in tumorigenesis, and activating oncogenic point mutations in the core pathway components Ras, Raf, or MEK are prevalent in many types of cancer. Intriguingly, however, analogous oncogenic mutations in the downstream effector kinase ERK have not been described or validated
    MeSH term(s) Animals ; Carcinogenesis/genetics ; Carcinogenesis/pathology ; Cell Proliferation/physiology ; Drosophila Proteins/genetics ; Drosophila melanogaster/genetics ; Drosophila melanogaster/metabolism ; Extracellular Signal-Regulated MAP Kinases/genetics ; Female ; Gain of Function Mutation ; Hyperplasia ; Male ; Membrane Proteins/genetics ; Neoplasms, Experimental/enzymology ; Neoplasms, Experimental/genetics ; Neoplasms, Experimental/metabolism ; Neoplasms, Experimental/pathology ; Point Mutation ; Signal Transduction
    Chemical Substances Drosophila Proteins ; Membrane Proteins ; Scrib protein, Drosophila ; Extracellular Signal-Regulated MAP Kinases (EC 2.7.11.24)
    Language English
    Publishing date 2019-11-18
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2167-2
    ISSN 1943-2631 ; 0016-6731
    ISSN (online) 1943-2631
    ISSN 0016-6731
    DOI 10.1534/genetics.119.302794
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.B 767: Show issues Location:
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