title: The function of FOXO1 in the late phases of the cell cycle is suppressed by PLK1-mediated phosphorylation.
abstract: Polo-like kinase 1 (PLK1) plays crucial roles in multiple stages of cell division. Our previous studies suggest that global transcriptional regulation by PLK1 may contribute to its multiple functions. PLK1 depletion is associated with a decrease in cell viability and the induction of apoptosis; however, the underlying mechanisms are not completely understood. Here, we report that forkhead box protein O1 (FOXO1) is a novel physiological substrate of PLK1. FOXO1 is at the interface of crucial cellular processes, orchestrating programs of gene expression that regulate apoptosis, cell cycle progression, and oxidative-stress resistance. PLK1 interacts with and phosphorylates FOXO1, mainly at the G 2/M phase of the cell cycle. PLK1-mediated phosphorylation leads to the impairment of FOXO1's transcriptional activity in an Akt-independent manner. By immunofluorescence staining and subcellular fractionation, we demonstrate that PLK1-induced FOXO1 phosphorylation causes its nuclear exclusion. Furthermore, PLK1-mediated phosphorylation of FOXO1 negatively regulates its pro-apoptotic function and abrogates its ability to delay entry into and progression through G 2/M transition. Therefore, our results suggest that PLK1 abrogates the inhibitory effects of FOXO1 on cell growth and survival to ensure timely cell cycle progression. This study not only reveals a novel and major regulatory mechanism of FOXO1 at the late phases of the cell cycle, but also provides new insight into the molecular mechanisms by which PLK1 inhibition leads to growth arrest and cell death.
authors.affiliation: Department of Human and Molecular Genetics; VCU Institute of Molecular Genetics; VCU Massey Cancer Center; Virginia Commonwealth University School of Medicine; Richmond, VA USA.
authors.forename: Chengfu
authors.initials: C
authors.lastname: Yuan
authors.affiliation: Department of Human and Molecular Genetics; VCU Institute of Molecular Genetics; VCU Massey Cancer Center; Virginia Commonwealth University School of Medicine; Richmond, VA USA; Sun Yat-Sen University; Guangzhou, PR China.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Human and Molecular Genetics; VCU Institute of Molecular Genetics; VCU Massey Cancer Center; Virginia Commonwealth University School of Medicine; Richmond, VA USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Human and Molecular Genetics; VCU Institute of Molecular Genetics; VCU Massey Cancer Center; Virginia Commonwealth University School of Medicine; Richmond, VA USA.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Fu
mesh_terms: D017209:Apoptosis; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D059565:G2 Phase Cell Cycle Checkpoints; D006801:Humans; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1; C085126:FOXO1 protein, human
keywords: FOXO1; PLK1; apoptosis; cell division; nuclear-cytoplasmic shuttling; phosphorylation; regulation; transcription factor