Drosophila VHL tumor-suppressor gene regulates epithelial morphogenesis by promoting microtubule and aPKC stability.
Mutations in the human von Hippel-Lindau (VHL) genes are the cause of VHL disease, which displays multiple benign and malignant tumors. The VHL gene has been shown to regulate angiogenic potential and glycolic metabolism via its E3 ubiquitin ligase function against the alpha subunit of hypoxia-inducible factor (HIF). However, many other HIF-independent functions of VHL have been identified and recent evidence indicates that the canonical function cannot fully explain the VHL mutant cell phenotypes. Many of these functions have not been verified in genetically tractable systems. Using an established follicular epithelial model in Drosophila, we show that the Drosophila VHL gene is involved in epithelial morphogenesis via stabilizing microtubule bundles and aPKC. Microtubule defects in VHL mutants lead to mislocalization of aPKC and subsequent loss of epithelial integrity. Destabilizing microtubules in ex vivo culture of wild-type egg chambers can also result in aPKC mislocalization and epithelial defects. Importantly, paclitaxel-induced stabilization of microtubules can rescue the aPKC localization phenotype in Drosophila VHL mutant follicle cells. The results establish a developmental function of the VHL gene that is relevant to its tumor-suppressor activity.
Duchi
Serena
S
Dipartimento di Biologia Evoluzionistica Sperimentale, Università di Bologna, Via Selmi 3, 40126 Bologna, Italy.
Fagnocchi
Luca
L
Cavaliere
Valeria
V
Hsouna
Anita
A
Gargiulo
Giuseppe
G
Hsu
Tien
T
D000818:Animals; D004330:Drosophila / Q000196:embryology* / Q000235:genetics*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004795:Enzyme Stability; D004848:Epithelium / Q000196:embryology*; D005260:Female; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D066298:In Vitro Techniques; D008297:Male; D018613:Microscopy, Confocal; D008870:Microtubules / Q000378:metabolism*; D006080:Ovarian Follicle / Q000166:cytology / Q000196:embryology; D051571:Protein Kinase C-alpha / Q000378:metabolism*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism*
D029721:Drosophila Proteins; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D051571:Protein Kinase C-alpha
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