title: RABL6A, a novel RAB-like protein, controls centrosome amplification and chromosome instability in primary fibroblasts.
abstract: RABL6A (RAB-like 6 isoform A) is a novel protein that was originally identified based on its association with the Alternative Reading Frame (ARF) tumor suppressor. ARF acts through multiple p53-dependent and p53-independent pathways to prevent cancer. How RABL6A functions, to what extent it depends on ARF and p53 activity, and its importance in normal cell biology are entirely unknown. We examined the biological consequences of RABL6A silencing in primary mouse embryo fibroblasts (MEFs) that express or lack ARF, p53 or both proteins. We found that RABL6A depletion caused centrosome amplification, aneuploidy and multinucleation in MEFs regardless of ARF and p53 status. The centrosome amplification in RABL6A depleted p53-/- MEFs resulted from centrosome reduplication via Cdk2-mediated hyperphosphorylation of nucleophosmin (NPM) at threonine-199. Thus, RABL6A prevents centrosome amplification through an ARF/p53-independent mechanism that restricts NPM-T199 phosphorylation. These findings demonstrate an essential role for RABL6A in centrosome regulation and maintenance of chromosome stability in non-transformed cells, key processes that ensure genomic integrity and prevent tumorigenesis.
authors.affiliation: Department of Pharmacology, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Zhang
authors.forename: Jussara
authors.initials: J
authors.lastname: Hagen
authors.forename: Viviane P
authors.initials: VP
authors.lastname: Muniz
authors.forename: Tarik
authors.initials: T
authors.lastname: Smith
authors.forename: Gary S
authors.initials: GS
authors.lastname: Coombs
authors.forename: Christine M
authors.initials: CM
authors.lastname: Eischen
authors.forename: Duncan I
authors.initials: DI
authors.lastname: Mackie
authors.forename: David L
authors.initials: DL
authors.lastname: Roman
authors.forename: Richard
authors.initials: R
authors.lastname: Van Rheeden
authors.forename: Benjamin
authors.initials: B
authors.lastname: Darbro
authors.forename: Van S
authors.initials: VS
authors.lastname: Tompkins
authors.forename: Dawn E
authors.initials: DE
authors.lastname: Quelle
mesh_terms: D020727:ADP-Ribosylation Factors / Q000378:metabolism / Q000502:physiology; D000818:Animals; D018385:Centrosome / Q000378:metabolism*; D043171:Chromosomal Instability; D005347:Fibroblasts / Q000378:metabolism; D055786:Gene Knockout Techniques; D020868:Gene Silencing; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism; D000090243:Nucleophosmin; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000502:physiology; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D000090243:Nucleophosmin; C000595658:RABL6A protein, human; C000594113:RABL6A protein, mouse; D020727:ADP-Ribosylation Factors; D020691:rab GTP-Binding Proteins