Centrosome-associated regulators of the G(2)/M checkpoint as targets for cancer therapy

Abstract

In eukaryotic cells, control mechanisms have developed that restrain cell-cycle transitions in response to stress. These regulatory pathways are termed cell-cycle checkpoints. The G(2)/M checkpoint prevents cells from entering mitosis when DNA is damaged in order to afford these cells an opportunity to repair the damaged DNA before propagating genetic defects to the daughter cells. If the damage is irreparable, checkpoint signaling might activate pathways that lead to apoptosis. Since alteration of cell-cycle control is a hallmark of tumorigenesis, cell-cycle regulators represent potential targets for therapy. The centrosome has recently come into focus as a critical cellular organelle that integrates G(2)/M checkpoint control and repairs signals in response to DNA damage. A growing number of G(2)/M checkpoint regulators have been found in the centrosome, suggesting that centrosome has an important role in G(2)/M checkpoint function. In this review, we discuss centrosome-associated regulators of the G(2)/M checkpoint, the dysregulation of this checkpoint in cancer, and potential candidate targets for cancer therapy.

Figure 1

Activation of the G2/M checkpoint after DNA damage. In response to DNA damage, the ATM, ATR signaling pathway is activated, which leads to the phosphorylation and activation of Chk1 and Chk2 and to the subsequent phosphorylation of Cdc25. Phosphorylated Cdc25 is sequestered in the cytoplasm by 14-3-3 proteins, which prevents activation of cyclinB/Cdk1 by Cdc25 and results in G2 arrest. Activated ATM/ATR also activates p53-dependent signaling. This contributes to the maintenance of G2 arrest by upregulating 14-3-3, which sequesters Cdk1 in the cytoplasm. In addition, p53 induces the transactivation of p21, a Cdk inhibitor that binds to and inhibits cyclinB/Cdk1 complexes. P: phosphorylation.