title: Nucleolar localization of a netrin-1 isoform enhances tumor cell proliferation.
abstract: Netrin-1 displays proto-oncogenic activity in several cancers, which is thought to be due to the ability of this secreted cue to stimulate survival when bound to its receptors. We showed that in contrast to full-length, secreted netrin-1, some cancer cells produced a truncated intranuclear form of netrin-1 (ΔN-netrin-1) through an alternative internal promoter. Because of a nucleolar localization signal located in its carboxyl terminus, ΔN-netrin-1 was targeted to the nucleolus, where it interacted with nucleolar proteins, affected nucleolar ultrastructure, and interacted with the promoters of ribosomal genes. Moreover, ΔN-netrin-1 stimulated cell proliferation in vitro and tumor growth in vivo. Thus, some cancer cells produce not only a full-length, secreted form of netrin-1 that promotes cell survival but also a truncated netrin-1 that stimulates cell proliferation, potentially by enhancing ribosome biogenesis.
authors.affiliation: Apoptosis, Cancer and Development Laboratory-Equipe labellisée La Ligue, LabEx DEVweCAN, Centre de Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, 69008 Lyon, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Delloye-Bourgeois
authors.forename: David
authors.initials: D
authors.lastname: Goldschneider
authors.forename: Andrea
authors.initials: A
authors.lastname: Paradisi
authors.forename: Gabriel
authors.initials: G
authors.lastname: Therizols
authors.forename: Stéphane
authors.initials: S
authors.lastname: Belin
authors.forename: Sabine
authors.initials: S
authors.lastname: Hacot
authors.forename: Manuel
authors.initials: M
authors.lastname: Rosa-Calatrava
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Scoazec
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Diaz
authors.forename: Agnès
authors.initials: A
authors.lastname: Bernet
authors.forename: Patrick
authors.initials: P
authors.lastname: Mehlen
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D045744:Cell Line, Tumor; D002466:Cell Nucleolus / Q000378:metabolism* / Q000648:ultrastructure; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002642:Chick Embryo; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D000075388:Netrin-1; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D014183:Transplantation, Heterologous; D047368:Tumor Burden; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; D020033:Protein Isoforms; D025521:Tumor Suppressor Proteins; D049452:Green Fluorescent Proteins; D000075388:Netrin-1