B23 regulates GADD45a nuclear translocation and contributes to GADD45a-induced cell cycle G2-M arrest.
Gadd45a is an important player in cell cycle G2-M arrest in response to genotoxic stress. However, the underlying mechanism(s) by which Gadd45a exerts its role in the control of cell cycle progression remains to be further defined. Gadd45a interacts with Cdc2, dissociates the Cdc2-cyclin B1 complex, alters cyclin B1 nuclear localization, and thus inhibits the activity of Cdc2/cyclin B1 kinase. These observations indicate that Gadd45a nuclear translocation is closely associated with its role in cell cycle G2-M arrest. Gadd45a has been characterized as a nuclear protein, but it does not contain a classical nuclear localization signal, suggesting that Gadd45a nuclear translocation might be mediated through different nuclear import machinery. Here we show that Gadd45a associates directly with B23 (nucleophosmin), and the B23-interacting domain is mapped at the central region (61-100 amino acids) of the Gadd45a protein using a series of Myc tag-Gadd45a deletion mutants. Deletion of this central region disrupts Gadd45a association with B23 and abolishes Gadd45a nuclear translocation. Suppression of endogenous B23 through a short interfering RNA approach disrupts Gadd45a nuclear translocation and results in impaired Gadd45a-induced cell cycle G2-M arrest. These findings demonstrate a novel association of B23 and Gadd45a and implicate B23 as an important regulator in Gadd45a nuclear import.
Gao
Hua
H
State Key Laboratory of Molecular Oncology, Cancer Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
Jin
Shunqian
S
Song
Yongmei
Y
Fu
Ming
M
Wang
Minrong
M
Liu
Zhihua
Z
Wu
Min
M
Zhan
Qimin
Q
D021581:Active Transport, Cell Nucleus; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002455:Cell Division; D004249:DNA Damage; D016195:G2 Phase; D045325:HCT116 Cells; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism* / Q000502:physiology*; D000090243:Nucleophosmin; D034741:RNA, Small Interfering / Q000494:pharmacology; D014466:Ultraviolet Rays; D000097642:GADD45 Proteins
D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D000090243:Nucleophosmin; D034741:RNA, Small Interfering; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C000716967:NPM1 protein, human