Cyclin B1/Cdk1 complex is the key regulator of mitosis in mammalian cells. In G2 phase, cyclinB1/Cdk1 accumulates in cytoplasm and on centrosomes, whereas Wee1/Myt kinases inactivate Cdk1 by phosphorylation of two residues of Cdk1: Thr14 and Tyr15.20 A key event in the activation of Cdk1 is the removal of the inhibitory phosphates. Cdc25 family members,

including Cdc25A, Cdc25B, and Cdc25C, can dephosphorylate both Thr14 and Tyr15 of Cdk1. Cdc25A and Cdc25B play an important role in M-phase entry,20 whereas Cdc25C is activated in mitosis via hyperphosphorylation by cyclin B1/Cdk1. The active Cdc25C triggers the activation of cyclin B1/Cdk1 complex GDC-0980 in vivo by the dephosphorylation of Thr14 and Tyr15 in Cdk1.21, 22 Therefore, Cdc25C plays a more prominent role in the proper execution of mitotic progression through up-regulating of Cdk1 activity. However, mitosis is an unstable cellular state and requires the continuous phosphorylation of multiple protein substrates CH5424802 ic50 to maintain its activation.23 The catalytic activity of Cdk1 is necessary and sufficient for maintaining the mitotic state of cells and

functions as a key switch for cell division.23 The loss of Cdk1 activity is the major factor to drive the exit of cells from mitosis and ensure the correct timing of mitosis exit.19, 24-27 Interestingly, one recent study suggests that decreasing Cdk1 activity during interphase could arrest cells at G2/M phase border, whereas decreasing Cdk1 activity in mitosis causes a faster mitotic exit and premature cytokinesis.23 This finding is in agreement with our data that TCTP could down-regulate Cdk1 activity via the inhibition of the dephosphorylation of Cdk1-Tyr15, as shown by an increase in Cdk1-Tyr15 level during mitotic progression, medchemexpress and leads to a faster mitotic exit. Inducible degradation of cell-cycle–regulatory proteins by the ubiquitin-proteasome pathway is one of the primary mechanisms governing passage through the cell cycle.28 Recent studies suggest that Cdc25C could be ubiquitinated during mitotic progression.29, 30 Here, we demonstrated that TCTP accelerated the ubiquitination-mediated degradation of Cdc25C during mitotic progression.

In mitosis, the mitotic checkpoint is the major cell-cycle control mechanism and is also the primary defense against chromosome instability (CIN), manifested as aneuploidy, which has been strictly linked to the development of cancer. Acceleration of mitotic exit often leads to chromosomal missegregation and aneuploid progeny.31 Thus, TCTP overexpression could induce impaired chromosome segregation by increasing the formation of lagging chromosomes during mitosis and increasing the hypertetraploid population. More important, faster M-phase exit, followed by abnormal chromosome segregation, cytokinesis, and CIN, could also be observed in cell populations derived from xenograft tumors induced by TCTP-7703, suggesting the direct association between the tumorigenicity of TCTP and its effects on mitosis regulation.