DISCOVERIES (ISSN 2359-7232),2014, April-June

CITATION: 
Bucur O, Stancu AL, Muraru MS, Melet A, Petrescu SM, Khosravi-Far R. PLK1 is a binding partner and a negative regulator of FOXO3 tumor suppressor. Discoveries 2014, Apr-Jun; 2(2): e16. DOI: 10.15190/d.2014.8

Submitted: March 21, 2014; Revised: June 26, 2014; Accepted: June 29, 2014; Published: June 30, 2014;

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PLK1 is a binding partner and a negative regulator of FOXO3 tumor suppressor

Octavian Bucur (1,2,#), Andreea Lucia Stancu (1,#) Maria Sinziana Muraru (1), Armelle Melet (3), Stefana Maria Petrescu (2), Roya Khosravi-Far (1,4,*),

(1) Department of Pathology, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA, USA;
(2) Institute of Biochemistry of the Romanian Academy, Bucharest, Romania;
(3) University Paris Descartes, Paris, France;
(4) Biological and Biomedical Sciences Program, Harvard Medical School, Boston, MA, USA;

# These authors contributed equally to this work; 
*Correspondence to: Prof. Roya Khosravi-Far, Department of Pathology, Harvard Medical School and Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA, 02215, USA. Tel: +1 617 372-2141; E-mail: rkhosrav@gmail.com;

Abstract

FOXO family members (FOXOs: FOXO1, FOXO3, FOXO4 and FOXO6) are important transcription factors and tumor suppressors controlling cell homeostasis and cell fate. They are characterized by an extraordinary functional diversity, being involved in regulation of cell cycle, proliferation, apoptosis, DNA damage response, oxidative detoxification, cell differentiation and stem cell maintenance, cell metabolism, angiogenesis, cardiac and other organ’s development, aging, and other critical cellular processes. FOXOs are tightly regulated by reversible phosphorylation, ubiquitination, acetylation and methylation. Interestingly, the known kinases phosphorylate only a small percentage of the known or predicted FOXOs phosphorylation sites, suggesting that additional kinases that phosphorylate and control FOXOs activity exist. In order to identify novel regulators of FOXO3, we have employed a proteomics screening strategy. Using HeLa cancer cell line and a Tandem Affinity Purification followed by Mass Spectrometry analysis, we identified several proteins as binding partners of FOXO3. Noteworthy, Polo Like Kinase 1 (PLK1) was one of the identified FOXO3 binding partners. PLK1 plays a critical role during cell cycle (G2-M transition and all phases of mitosis) and in maintenance of genomic stability. Our experimental results presented in this manuscript demonstrate that FOXO3 and PLK1 exist in a molecular complex through most of the phases of the cell cycle, with a higher occurrence in the G2-M cell cycle phases. PLK1 induces translocation of FOXO3 from the nucleus to the cytoplasm and suppresses FOXO3 activity, measured by the decrease in the pro-apoptotic Bim protein levels and in the cell cycle inhibitor protein p27. Furthermore, PLK1 can directly phosphorylate FOXO3 in an in vitro kinase assay. These results present the discovery of PLK1 as a binding partner and a negative regulator of FOXO3 proteins.

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