title: Drosophila VHL tumor-suppressor gene regulates epithelial morphogenesis by promoting microtubule and aPKC stability.
abstract: 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.
authors.affiliation: Dipartimento di Biologia Evoluzionistica Sperimentale, Università di Bologna, Via Selmi 3, 40126 Bologna, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Duchi
authors.forename: Luca
authors.initials: L
authors.lastname: Fagnocchi
authors.forename: Valeria
authors.initials: V
authors.lastname: Cavaliere
authors.forename: Anita
authors.initials: A
authors.lastname: Hsouna
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Gargiulo
authors.forename: Tien
authors.initials: T
authors.lastname: Hsu
mesh_terms: 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*
chemical_list: D029721:Drosophila Proteins; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D051571:Protein Kinase C-alpha
references.citation: J Cell Sci. 2006 Oct 15;119(Pt 20):4155-63
references.pmid: 17038542
references.citation: Nat Cell Biol. 2008 Oct;10(10):1208-16
references.pmid: 18806787
references.citation: Development. 2008 Feb;135(3):463-71
references.pmid: 18094021
references.citation: J Cell Biol. 2006 Nov 20;175(4):547-54
references.pmid: 17101696
references.citation: Cell Cycle. 2006 Sep;5(18):2054-6
references.pmid: 16969113
references.citation: Bioessays. 2002 Aug;24(8):690-5
references.pmid: 12210528
references.citation: Oncogene. 2004 Nov 11;23(53):8688-94
references.pmid: 15467749
references.citation: J Cell Sci. 1993 Aug;105 ( Pt 4):993-1000
references.pmid: 8227220
references.citation: Nat Rev Cancer. 2008 Nov;8(11):865-73
references.pmid: 18923434
references.citation: Cell. 1995 Jul 14;82(1):67-76
references.pmid: 7606787
references.citation: Cancer Res. 2002 May 15;62(10):2929-36
references.pmid: 12019174
references.citation: Nat Cell Biol. 2003 Jan;5(1):53-8
references.pmid: 12510194
references.citation: Cancer Res. 2006 Feb 1;66(3):1553-60
references.pmid: 16452212
references.citation: Nat Cell Biol. 2008 Mar;10(3):361-9
references.pmid: 18297059
references.citation: Mol Cell. 1998 Jun;1(7):959-68
references.pmid: 9651579
references.citation: Nat Protoc. 2007;2(10):2467-73
references.pmid: 17947988
references.citation: Nature. 1999 Dec 2;402(6761):544-7
references.pmid: 10591216
references.citation: Dev Cell. 2007 May;12(5):727-38
references.pmid: 17488624
references.citation: Dev Cell. 2004 Jun;6(6):845-54
references.pmid: 15177032
references.citation: Cell. 1990 Jun 1;61(5):787-99
references.pmid: 2344615
references.citation: J Biol Chem. 2006 Apr 28;281(17):12069-80
references.pmid: 16505488
references.citation: Genes Dev. 2002 Jun 15;16(12):1568-81
references.pmid: 12080094
references.citation: Curr Biol. 2005 Feb 8;15(3):276-82
references.pmid: 15694314
references.citation: Biochem J. 2006 Jan 15;393(Pt 2):471-80
references.pmid: 16176182
references.citation: J Am Soc Nephrol. 2006 Jul;17(7):1801-6
references.pmid: 16775032
references.citation: Dev Biol. 1994 Oct;165(2):352-60
references.pmid: 7958405
references.citation: Traffic. 2004 Jan;5(1):1-9
references.pmid: 14675420
references.citation: Science. 2000 Jun 16;288(5473):2013-8
references.pmid: 10856208
references.citation: J Cell Biol. 2000 Nov 13;151(4):891-904
references.pmid: 11076972
references.citation: Curr Biol. 2003 Apr 29;13(9):734-43
references.pmid: 12725730
references.citation: Biochem Biophys Res Commun. 2000 Sep 16;276(1):355-61
references.pmid: 11006129
references.citation: Cancer Res. 2006 Jul 15;66(14):6903-7
references.pmid: 16849532
references.citation: Nat Cell Biol. 2009 Aug;11(8):994-1001
references.pmid: 19620968
references.citation: Development. 1997 Oct;124(19):3871-80
references.pmid: 9367443
references.citation: Development. 1993 Apr;117(4):1223-37
references.pmid: 8404527
references.citation: Oncogene. 2000 Jun 1;19(24):2803-11
references.pmid: 10851083
references.citation: Mol Biol Cell. 2009 Feb;20(3):1089-101
references.pmid: 19073886
references.citation: J Cell Sci. 2006 Mar 15;119(Pt 6):979-87
references.pmid: 16525119
references.citation: FEBS Lett. 2007 Oct 2;581(24):4571-6
references.pmid: 17825299
references.citation: Nat Cell Biol. 2003 Jan;5(1):64-70
references.pmid: 12510195
references.citation: Nat Rev Mol Cell Biol. 2005 Mar;6(3):233-47
references.pmid: 15738988
references.citation: Cancer Res. 2008 Jun 15;68(12):4649-57
references.pmid: 18559510
references.citation: J Cell Biol. 2004 Aug 16;166(4):549-57
references.pmid: 15302858
references.citation: Nat Cell Biol. 2003 Jan;5(1):46-52
references.pmid: 12510193
references.citation: Eur J Hum Genet. 2008 Jan;16(1):73-8
references.pmid: 17912253
references.citation: Curr Opin Cell Biol. 2007 Dec;19(6):685-90
references.pmid: 18006292
references.citation: Mol Cell. 2007 Oct 12;28(1):15-27
references.pmid: 17936701
references.citation: Science. 2002 Dec 6;298(5600):1955-9
references.pmid: 12471248
references.citation: Exp Cell Res. 2004 Dec 10;301(2):139-46
references.pmid: 15530850
references.citation: Dev Biol. 2009 May 15;329(2):294-305
references.pmid: 19285057
references.citation: Nature. 2003 Apr 17;422(6933):766-74
references.pmid: 12700771