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1.
EMBO Rep ; 21(4): e49700, 2020 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-32030856

RESUMO

Epithelial cells undergo cortical rounding at the onset of mitosis to enable spindle orientation in the plane of the epithelium. In cuboidal epithelia in culture, the adherens junction protein E-cadherin recruits Pins/LGN/GPSM2 and Mud/NuMA to orient the mitotic spindle. In the pseudostratified columnar epithelial cells of Drosophila, septate junctions recruit Mud/NuMA to orient the spindle, while Pins/LGN/GPSM2 is surprisingly dispensable. We show that these pseudostratified epithelial cells downregulate E-cadherin as they round up for mitosis. Preventing cortical rounding by inhibiting Rho-kinase-mediated actomyosin contractility blocks downregulation of E-cadherin during mitosis. Mitotic activation of Rho-kinase depends on the RhoGEF ECT2/Pebble and its binding partners RacGAP1/MgcRacGAP/CYK4/Tum and MKLP1/KIF23/ZEN4/Pav. Cell cycle control of these Rho activators is mediated by the Aurora A and B kinases, which act redundantly during mitotic rounding. Thus, in Drosophila pseudostratified epithelia, disruption of adherens junctions during mitosis necessitates planar spindle orientation by septate junctions to maintain epithelial integrity.


Assuntos
Junções Aderentes , Fuso Acromático , Animais , Drosophila/genética , Células Epiteliais , Mitose
2.
Semin Cell Dev Biol ; 28: 70-7, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24583474

RESUMO

Human colorectal cancers arise as benign adenomas, tumours that retain their epithelial character, and then progress to malignant adenocarcinomas and carcinomas in which the epithelium becomes disrupted. Carcinomas often exhibit transcriptional downregulation of E-cadherin and other epithelial genes in an epithelial-to-mesenchymal transition (EMT), a mechanism first discovered in Drosophila to be mediated by the transcription factors Twist and Snail. In contrast, adenocarcinomas retain expression of E-cadherin and disruption of the epithelium occurs through formation of progressively smaller epithelial cysts with apical Crumbs/CRB3, Stardust/PALS1, and Bazooka/PAR3 localised to the inner lumen. Results from Drosophila show that morphologically similar cysts form upon induction of clonal heterogeneity in Wnt, Smad, or Ras signalling levels, which causes extrusion of epithelial cells at clonal boundaries. Thus, intratumour heterogeneity might also promote formation of adenocarcinomas in humans. Finally, epithelial cysts can collectively migrate, as in the case of Drosophila border cells, a potential model system for the invasive migration of adenocarcinoma cells.


Assuntos
Caderinas/metabolismo , Neoplasias Colorretais/metabolismo , Epitélio/metabolismo , Transdução de Sinais/fisiologia , Fatores de Transcrição/metabolismo , Animais , Movimento Celular/fisiologia , Drosophila , Epitélio/patologia , Humanos
5.
Curr Biol ; 25(1): 61-8, 2015 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-25484300

RESUMO

The Lethal giant larvae (Lgl) protein was discovered in Drosophila as a tumor suppressor in both neural stem cells (neuroblasts) and epithelia. In neuroblasts, Lgl relocalizes to the cytoplasm at mitosis, an event attributed to phosphorylation by mitotically activated aPKC kinase and thought to promote asymmetric cell division. Here we show that Lgl also relocalizes to the cytoplasm at mitosis in epithelial cells, which divide symmetrically. The Aurora A and B kinases directly phosphorylate Lgl to promote its mitotic relocalization, whereas aPKC kinase activity is required only for polarization of Lgl. A form of Lgl that is a substrate for aPKC, but not Aurora kinases, can restore cell polarity in lgl mutants but reveals defects in mitotic spindle orientation in epithelia. We propose that removal of Lgl from the plasma membrane at mitosis allows Pins/LGN to bind Dlg and thus orient the spindle in the plane of the epithelium. Our findings suggest a revised model for Lgl regulation and function in both symmetric and asymmetric cell divisions.


Assuntos
Aurora Quinases/metabolismo , Proteínas de Drosophila/metabolismo , Células Epiteliais/fisiologia , Mitose , Proteína Quinase C/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Citoplasma/metabolismo , Drosophila , Células-Tronco Neurais/fisiologia , Fosforilação , Fuso Acromático/fisiologia , Asas de Animais/crescimento & desenvolvimento
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