SUMOylation inhibits FOXM1 activity and delays mitotic transition

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Title: SUMOylation inhibits FOXM1 activity and delays mitotic transition
Authors: Myatt, SS
Kongsema, M
Man, CW-Y
Kelly, DJ
Gomes, AR
Khongkow, P
Karunarathna, U
Zona, S
Langer, JK
Dunsby, CW
Coombes, RC
French, PM
Brosens, JJ
Lam, EW-F
Item Type: Journal Article
Abstract: The forkhead box transcription factor FOXM1 is an essential effector of G2/M-phase transition, mitosis and the DNA damage response. As such, it is frequently deregulated during tumorigenesis. Here we report that FOXM1 is dynamically modified by SUMO1 but not by SUMO2/3 at multiple sites. We show that FOXM1 SUMOylation is enhanced in MCF-7 breast cancer cells in response to treatment with epirubicin and mitotic inhibitors. Mutation of five consensus conjugation motifs yielded a SUMOylation-deficient mutant FOXM1. Conversely, fusion of the E2 ligase Ubc9 to FOXM1 generated an auto-SUMOylating mutant (FOXM1-Ubc9). Analysis of wild-type FOXM1 and mutants revealed that SUMOylation inhibits FOXM1 activity, promotes translocation to the cytoplasm and enhances APC/Cdh1-mediated ubiquitination and degradation. Further, expression of the SUMOylation-deficient mutant enhanced cell proliferation compared with wild-type FOXM1, whereas the FOXM1-Ubc9 fusion protein resulted in persistent cyclin B1 expression and slowed the time from mitotic entry to exit. In summary, our findings suggest that SUMOylation attenuates FOXM1 activity and causes mitotic delay in cytotoxic drug response.
Issue Date: 23-Dec-2013
Date of Acceptance: 18-Nov-2013
URI: http://hdl.handle.net/10044/1/39236
DOI: http://dx.doi.org/10.1038/onc.2013.546
ISSN: 1476-5594
Publisher: Nature Publishing Group
Start Page: 4316
End Page: 4329
Journal / Book Title: Oncogene
Volume: 33
Issue: 34
Copyright Statement: This work is licensed under a Creative Commons Attribution 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by/3.0/.
Sponsor/Funder: Cancer Research UK
Funder's Grant Number: C37/A12011
Keywords: Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Oncology
Cell Biology
Genetics & Heredity
FOXM1
SUMO
chemotherapy
drug resistance
breast cancer
cell cycle
BREAST-CANCER
TRANSCRIPTION FACTOR
POSTTRANSLATIONAL MODIFICATION
EPIRUBICIN TREATMENT
UBIQUITIN LIGASE
DNA-DAMAGE
E3 LIGASE
B-MYB
EXPRESSION
Antibiotics, Antineoplastic
Binding Sites
Cadherins
Cell Proliferation
Cytoplasm
Drug Resistance, Neoplasm
Epirubicin
Forkhead Transcription Factors
G2 Phase Cell Cycle Checkpoints
HeLa Cells
Humans
MCF-7 Cells
Mitosis
Nocodazole
Protein Transport
Proteolysis
SUMO-1 Protein
Sumoylation
Hela Cells
Cytoplasm
Humans
Nocodazole
Epirubicin
Cadherins
SUMO-1 Protein
Antibiotics, Antineoplastic
Mitosis
Cell Proliferation
Binding Sites
Protein Transport
Drug Resistance, Neoplasm
Forkhead Transcription Factors
Sumoylation
Proteolysis
G2 Phase Cell Cycle Checkpoints
MCF-7 Cells
Oncology & Carcinogenesis
1112 Oncology And Carcinogenesis
1103 Clinical Sciences
Publication Status: Published
Appears in Collections:Physics
Division of Surgery
Photonics
Division of Cancer
Faculty of Medicine
Faculty of Natural Sciences



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