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  1. Article ; Online: The Drosophila metastasis suppressor gene Nm23 homolog, awd, regulates epithelial integrity during oogenesis.

    Woolworth, Julie A / Nallamothu, Gouthami / Hsu, Tien

    Molecular and cellular biology

    2009  Volume 29, Issue 17, Page(s) 4679–4690

    Abstract: The expression levels of the metastasis suppressor gene Nm23 have been shown to correlate positively or inversely with prognosis in different cancer cohorts. This indicates that Nm23 may be needed at different expression levels and may function ... ...

    Abstract The expression levels of the metastasis suppressor gene Nm23 have been shown to correlate positively or inversely with prognosis in different cancer cohorts. This indicates that Nm23 may be needed at different expression levels and may function differently in various tissues. Here we report a novel epithelial function of the Drosophila melanogaster homolog of human Nm23, abnormal wing discs (awd). We show a dynamic expression pattern of the Awd protein during morphogenesis of the Drosophila follicle cells during oogenesis. Loss-of-function awd mutant cells result in the accumulation and spreading of adherens junction components, such as Drosophila E-cadherin, beta-catenin/Armadillo, and alpha-spectrin, and the disruption of epithelial integrity, including breaking up of the epithelial sheet and piling up of follicle cells. In contrast, overexpression of awd diminishes adherens junction components and induces a mesenchymal-cell-like cell shape change. The gain-of-function phenotype is consistent with a potential oncogenic function of this metastasis suppressor gene. Interestingly, we demonstrate that the epithelial function of awd is mediated by Rab5 and show that the Rab5 expression level is downregulated in awd mutant cells. Therefore, awd modulates the level and localization of adherens junction components via endocytosis. This is the first demonstration of an in vivo function of Nm23 family genes in regulating epithelial morphogenesis.
    MeSH term(s) Adherens Junctions/metabolism ; Animals ; Animals, Genetically Modified ; Drosophila Proteins/genetics ; Drosophila Proteins/metabolism ; Drosophila melanogaster/anatomy & histology ; Drosophila melanogaster/embryology ; Drosophila melanogaster/physiology ; Epithelium/anatomy & histology ; Epithelium/embryology ; Female ; Genes, Tumor Suppressor ; Humans ; Morphogenesis/physiology ; Nucleoside-Diphosphate Kinase/genetics ; Nucleoside-Diphosphate Kinase/metabolism ; Oogenesis/physiology ; Ovary/anatomy & histology ; Ovary/metabolism ; Phenotype ; Recombinant Fusion Proteins/genetics ; Recombinant Fusion Proteins/metabolism ; rab5 GTP-Binding Proteins/genetics ; rab5 GTP-Binding Proteins/metabolism
    Chemical Substances Drosophila Proteins ; Recombinant Fusion Proteins ; Nucleoside-Diphosphate Kinase (EC 2.7.4.6) ; awd protein, Drosophila (EC 2.7.4.6) ; rab5 GTP-Binding Proteins (EC 3.6.5.2)
    Language English
    Publishing date 2009-07-06
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 779397-2
    ISSN 1098-5549 ; 0270-7306
    ISSN (online) 1098-5549
    ISSN 0270-7306
    DOI 10.1128/MCB.00297-09
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1666: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
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    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  2. Article ; Online: Notch signaling during development requires the function of awd, the Drosophila homolog of human metastasis suppressor gene Nm23.

    Ignesti, Marilena / Barraco, Marilena / Nallamothu, Gouthami / Woolworth, Julie A / Duchi, Serena / Gargiulo, Giuseppe / Cavaliere, Valeria / Hsu, Tien

    BMC biology

    2014  Volume 12, Page(s) 12

    Abstract: Background: The Drosophila abnormal wing discs (awd) belongs to a highly conserved family of genes implicated in metastasis suppression, metabolic homeostasis and epithelial morphogenesis. The cellular function of the mammalian members of this family, ... ...

    Abstract Background: The Drosophila abnormal wing discs (awd) belongs to a highly conserved family of genes implicated in metastasis suppression, metabolic homeostasis and epithelial morphogenesis. The cellular function of the mammalian members of this family, the Nm23 proteins, has not yet been clearly defined. Previous awd genetic analyses unraveled its endocytic role that is required for proper internalization of receptors controlling different signaling pathways. In this study, we analyzed the role of Awd in controlling Notch signaling during development.
    Results: To study the awd gene function we used genetic mosaic approaches to obtain cells homozygous for a loss of function allele. In awd mutant follicle cells and wing disc cells, Notch accumulates in enlarged early endosomes, resulting in defective Notch signaling. Our results demonstrate that awd function is required before γ-secretase mediated cleavage since over-expression of the constitutively active form of the Notch receptor in awd mutant follicle cells allows rescue of the signaling. By using markers of different endosomal compartments we show that Notch receptor accumulates in early endosomes in awd mutant follicle cells. A trafficking assay in living wing discs also shows that Notch accumulates in early endosomes. Importantly, constitutively active Rab5 cannot rescue the awd phenotype, suggesting that awd is required for Rab5 function in early endosome maturation.
    Conclusions: In this report we demonstrate that awd is essential for Notch signaling via its endocytic role. In addition, we identify the endocytic step at which Awd function is required for Notch signaling and we obtain evidence indicating that Awd is necessary for Rab5 function. These findings provide new insights into the developmental and pathophysiological function of this important gene family.
    MeSH term(s) Animals ; Cell Proliferation ; Clone Cells ; Cytoplasmic Vesicles ; Drosophila Proteins/metabolism ; Drosophila melanogaster/genetics ; Drosophila melanogaster/growth & development ; Drosophila melanogaster/metabolism ; Endocytosis ; Endosomes/metabolism ; Female ; Gene Expression Regulation, Developmental ; Humans ; Imaginal Discs/cytology ; Larva/growth & development ; Larva/metabolism ; Mutation/genetics ; NM23 Nucleoside Diphosphate Kinases/genetics ; NM23 Nucleoside Diphosphate Kinases/metabolism ; Neoplasm Metastasis ; Nucleoside-Diphosphate Kinase/metabolism ; Ovarian Follicle/cytology ; Ovarian Follicle/metabolism ; Protein Transport ; Receptors, Notch/metabolism ; Sequence Homology, Amino Acid ; Signal Transduction ; Wings, Animal/cytology ; Wings, Animal/metabolism ; rab5 GTP-Binding Proteins/metabolism
    Chemical Substances Drosophila Proteins ; N protein, Drosophila ; NM23 Nucleoside Diphosphate Kinases ; Receptors, Notch ; NME1 protein, human (EC 2.7.4.6) ; Nucleoside-Diphosphate Kinase (EC 2.7.4.6) ; awd protein, Drosophila (EC 2.7.4.6) ; Rab5 protein, Drosophila (EC 3.6.1.47.) ; rab5 GTP-Binding Proteins (EC 3.6.5.2)
    Language English
    Publishing date 2014-02-14
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2133020-7
    ISSN 1741-7007 ; 1741-7007
    ISSN (online) 1741-7007
    ISSN 1741-7007
    DOI 10.1186/1741-7007-12-12
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Awd, the homolog of metastasis suppressor gene Nm23, regulates Drosophila epithelial cell invasion.

    Nallamothu, Gouthami / Woolworth, Julie A / Dammai, Vincent / Hsu, Tien

    Molecular and cellular biology

    2008  Volume 28, Issue 6, Page(s) 1964–1973

    Abstract: Border cell migration during Drosophila melanogaster oogenesis is a highly pliable model for studying epithelial to mesenchymal transition and directional cell migration. The process involves delamination of a group of 6 to 10 follicle cells from the ... ...

    Abstract Border cell migration during Drosophila melanogaster oogenesis is a highly pliable model for studying epithelial to mesenchymal transition and directional cell migration. The process involves delamination of a group of 6 to 10 follicle cells from the epithelium followed by guided migration and invasion through the nurse cell complex toward the oocyte. The guidance cue is mainly provided by the homolog of platelet-derived growth factor/vascular endothelial growth factor family of growth factor, or Pvf, emanating from the oocyte, although Drosophila epidermal growth factor receptor signaling also plays an auxiliary role. Earlier studies implicated a stringent control of the strength of Pvf-mediated signaling since both down-regulation of Pvf and overexpression of active Pvf receptor (Pvr) resulted in stalled border cell migration. Here we show that the metastasis suppressor gene homolog Nm23/awd is a negative regulator of border cell migration. Its down-regulation allows for optimal spatial signaling from two crucial pathways, Pvr and JAK/STAT. Its overexpression in the border cells results in stalled migration and can revert the phenotype of overexpressing constitutive Pvr or dominant-negative dynamin. This is a rare example demonstrating the relevance of a metastasis suppressor gene function utilized in a developmental process involving cell invasion.
    MeSH term(s) Animals ; Animals, Genetically Modified ; Cell Movement ; Down-Regulation ; Drosophila Proteins/biosynthesis ; Drosophila Proteins/deficiency ; Drosophila Proteins/genetics ; Drosophila Proteins/physiology ; Dynamins/deficiency ; Dynamins/genetics ; Dynamins/physiology ; Endocytosis ; Epithelial Cells/physiology ; Female ; Gene Expression Regulation, Developmental ; MAP Kinase Signaling System/physiology ; Nucleoside-Diphosphate Kinase/biosynthesis ; Nucleoside-Diphosphate Kinase/deficiency ; Nucleoside-Diphosphate Kinase/genetics ; Nucleoside-Diphosphate Kinase/physiology ; Ovary/cytology ; Promoter Regions, Genetic ; Receptor Protein-Tyrosine Kinases/physiology ; Receptors, Interleukin/genetics ; Receptors, Interleukin/physiology ; Recombinant Fusion Proteins/physiology ; Signal Transduction/physiology
    Chemical Substances Drosophila Proteins ; Receptors, Interleukin ; Recombinant Fusion Proteins ; dome protein, Drosophila ; Pvr protein, Drosophila (EC 2.7.10.1) ; Receptor Protein-Tyrosine Kinases (EC 2.7.10.1) ; Nucleoside-Diphosphate Kinase (EC 2.7.4.6) ; awd protein, Drosophila (EC 2.7.4.6) ; Dynamins (EC 3.6.5.5) ; shi protein, Drosophila (EC 3.6.5.5)
    Language English
    Publishing date 2008-01-22
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 779397-2
    ISSN 1098-5549 ; 0270-7306
    ISSN (online) 1098-5549
    ISSN 0270-7306
    DOI 10.1128/MCB.01743-07
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1666: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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