SUMOylation inhibits FOXM1 activity and delays mitotic transition
File(s)
Author(s)
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.
Date Issued
2013-12-23
Date Acceptance
2013-11-18
Citation
Oncogene, 2013, 33 (34), pp.4316-4329
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/.
License URL
Sponsor
Cancer Research UK
Grant Number
C37/A12011
Subjects
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
Oncology & Carcinogenesis
1112 Oncology And Carcinogenesis
1103 Clinical Sciences
Publication Status
Published