title: Polo-like kinase 1-mediated phosphorylation of Forkhead box protein M1b antagonizes its SUMOylation and facilitates its mitotic function.
abstract: Transcription factor Forkhead box protein M1b (FoxM1b) plays an important role during mitotic entry and progression. Our previous studies identified polo-like kinase 1 (PLK1) as a major regulator of FoxM1b. During G2/M transition, PLK1 directly interacts with and phosphorylates FoxM1b, resulting in full activation of the transactivation capacity of FoxM1b. Such a vital regulatory mechanism is essential for timely mitotic entry and progression. However, the molecular mechanism by which PLK1-mediated phosphorylation enhances the transcriptional activity of FoxM1b remains to be determined. We demonstrate that FoxM1b can be SUMOylated in vitro and in vivo, preferentially by SUMO-1. SUMOylation of FoxM1b was found to occur at multiple sites, leading to suppression of FoxM1b transcriptional activity. Such a posttranslational modification of FoxM1b was antagonized by PLK1-mediated phosphorylation. By immunofluorescence staining and subcellular fractionation, we demonstrate that SUMO conjugation promotes cytosolic translocation of FoxM1b. Moreover, SUMO modification of FoxM1b facilitates the ubiquitin-mediated proteasomal degradation of FoxM1b. PLK1-mediated phosphorylation of FoxM1b abrogates the inhibitory effect on FoxM1b by SUMO modification, thereby promoting its nuclear translocation and preventing its proteolytic degradation in the cytoplasm. Such an antagonistic regulatory mechanism is essential for the mitotic function of FoxM1b, ensuring timely mitotic entry and progression. Taken together, our studies have revealed a working mechanism by which PLK1 positively regulates the activity and level of FoxM1b, which would greatly facilitate therapeutic interventions that focus on targeting the PLK1-mediated and/or FoxM1-mediated signaling network.
authors.affiliation: From the Department of Human and Molecular Genetics, Virginia Commonwealth University Institute of Molecular Genetics, Virginia Commonwealth University Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298.
authors.forename: Jinglei
authors.initials: J
authors.lastname: Zhang
authors.affiliation: From the Department of Human and Molecular Genetics, Virginia Commonwealth University Institute of Molecular Genetics, Virginia Commonwealth University Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298.
authors.forename: Chengfu
authors.initials: C
authors.lastname: Yuan
authors.affiliation: From the Department of Human and Molecular Genetics, Virginia Commonwealth University Institute of Molecular Genetics, Virginia Commonwealth University Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Wu
authors.affiliation: From the Department of Human and Molecular Genetics, Virginia Commonwealth University Institute of Molecular Genetics, Virginia Commonwealth University Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298.
authors.forename: Zeinab
authors.initials: Z
authors.lastname: Elsayed
authors.affiliation: From the Department of Human and Molecular Genetics, Virginia Commonwealth University Institute of Molecular Genetics, Virginia Commonwealth University Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298 zfu@vcu.edu.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Fu
mesh_terms: D021581:Active Transport, Cell Nucleus; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008938:Mitosis; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D059748:Proteolysis; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D025842:SUMO-1 Protein / Q000378:metabolism; D058207:Sumoylation; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D025842:SUMO-1 Protein; D000097869:Polo-Like Kinase 1; C107585:FOXM1 protein, human
keywords: Cell Cycle; FoxM1b; Mitosis; Nuclear-Cytoplasmic Shuttling; PLK1; Phosphorylation; Protein Stability; Regulation; SUMOylation; Transcription Factor