title: Regulation of cell cycle progression by forkhead transcription factor FOXO3 through its binding partner DNA replication factor Cdt1.
abstract: To ensure genome stability, DNA must be replicated once and only once during each cell cycle. Cdt1 is tightly regulated to make sure that cells do not rereplicate their DNA. Multiple regulatory mechanisms operate to ensure degradation of Cdt1 in S phase. However, little is known about the positive regulators of Cdt1 under physiological conditions. Here we identify FOXO3 as a binding partner of Cdt1. FOXO3 forms a protein complex with Cdt1, which in turn blocks its interaction with DDB1 and PCNA. Conversely, FOXO3 depletion facilitated the proteolysis of Cdt1 in unperturbed cells. Intriguingly, FOXO3 deficiency resulted in impaired S-phase entry and reduced cell proliferation. We provide data that FOXO3 knockdown mimics Cdt1 down-regulation and affects G1/S transitions. Our results demonstrate a unique role of FOXO3 in binding to Cdt1 and maintaining its level required for cell cycle progression.
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences,  Xiamen University, Xiamen, Fujian 361005,  China.
authors.forename: Yiru
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yuqian
authors.initials: Y
authors.lastname: Xing
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Yang
authors.initials: Y
authors.lastname: Mei
authors.forename: Kazuo
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
authors.forename: Han
authors.initials: H
authors.lastname: You
mesh_terms: D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation; D044842:Cullin Proteins / Q000378:metabolism; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D016193:G1 Phase; D064248:Geminin; D006801:Humans; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011485:Protein Binding; D055550:Protein Stability; D016196:S Phase; D054875:Ubiquitination
chemical_list: C467199:CDT1 protein, human; C114234:CUL4A protein, human; D018797:Cell Cycle Proteins; D044842:Cullin Proteins; C091435:DDB1 protein, human; D004268:DNA-Binding Proteins; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C577995:GMNN protein, human; D064248:Geminin; D018809:Proliferating Cell Nuclear Antigen