RABL6A, a novel RAB-like protein, controls centrosome amplification and chromosome instability in primary fibroblasts

Xuefeng Zhang; Jussara Hagen; Viviane P Muniz; Tarik Smith; Gary S Coombs; Christine M Eischen; Duncan I Mackie; David L Roman; Richard Van Rheeden; Benjamin Darbro; Van S Tompkins; Dawn E Quelle

doi:10.1371/journal.pone.0080228

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RABL6A, a novel RAB-like protein, controls centrosome amplification and chromosome instability in primary fibroblasts

Journal article

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RABL6A, a novel RAB-like protein, controls centrosome amplification and chromosome instability in primary fibroblasts

Xuefeng Zhang, Jussara Hagen, Viviane P Muniz, Tarik Smith, Gary S Coombs, Christine M Eischen, Duncan I Mackie, David L Roman, Richard Van Rheeden, Benjamin Darbro, …

PloS one, Vol.8(11), pp.e80228-e80228

2013

DOI: 10.1371/journal.pone.0080228

PMCID: PMC3839920

PMID: 24282525

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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.

rab GTP-Binding Proteins - metabolism

Oncogene Proteins - genetics

Humans

Gene Silencing

Oncogene Proteins - metabolism

Tumor Suppressor Protein p53 - metabolism

Nuclear Proteins - metabolism

rab GTP-Binding Proteins - genetics

Gene Knockout Techniques

Oncogene Proteins - physiology

Centrosome - metabolism

Tumor Suppressor Protein p53 - physiology

rab GTP-Binding Proteins - physiology

Animals

ADP-Ribosylation Factors - physiology

Mice

ADP-Ribosylation Factors - metabolism

Chromosomal Instability

Fibroblasts - metabolism

Details

Title: Subtitle: RABL6A, a novel RAB-like protein, controls centrosome amplification and chromosome instability in primary fibroblasts
Creators: Xuefeng Zhang - Department of Pharmacology, University of Iowa, Iowa City, Iowa, United States of America
Jussara Hagen
Viviane P Muniz
Tarik Smith
Gary S Coombs
Christine M Eischen
Duncan I Mackie
David L Roman
Richard Van Rheeden
Benjamin Darbro
Van S Tompkins
Dawn E Quelle
Resource Type: Journal article
Publication Details: PloS one, Vol.8(11), pp.e80228-e80228
DOI: 10.1371/journal.pone.0080228
PMID: 24282525
PMCID: PMC3839920
NLM abbreviation: PLoS One
ISSN: 1932-6203
eISSN: 1932-6203
Publisher: Public Library of Science; United States
Grant note: R21 CA127031 / NCI NIH HHS CA090367 / NCI NIH HHS CA127031 / NCI NIH HHS R01 CA090367 / NCI NIH HHS
Language: English
Date published: 2013
Academic Unit: Pharmacy; Molecular Physiology and Biophysics; Stead Family Department of Pediatrics; Pathology; Iowa Neuroscience Institute; Pharmaceutical Sciences and Experimental Therapeutics; Medical Genetics and Genomics; Neuroscience and Pharmacology; Biochemistry and Molecular Biology; Medicinal and Natural Products Chemistry
Record Identifier: 9984040281502771

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