Regulation of the p53-MDM2 pathway by 14-3-3 sigma and other proteins.

The 14-3-3 sigma (sigma) protein, a unique member of 14-3-3 family, is a negative regulator of the cell cycle and is induced by p53 to initiate cell cycle checkpoint control after DNA damage. Among the 14-3-3 family members, 14-3-3 sigma is uniquely induced by p53 and has a positive feedback effect on p53 activity in response to DNA damage. Although 14-3-3 sigma is linked to p53-regulated cell cycle checkpoint control, the detailed mechanisms of cell cycle regulation by 14-3-3 sigma remain unclear. Decreased expression of 14-3-3 sigma was reported in several types of carcinomas, suggesting that the negative regulatory role of 14-3-3 sigma in the cell cycle is compromised during tumorigenesis. Given the fact that p53's tumor suppressive function is lost in almost half of all human cancers and that 14-3-3 sigma's activity is linked to the p53 network, a perspective regarding the p53/14-3-3 sigma relationship is needed for cancer research. Here we discuss the mechanisms by which 14-3-3 sigma-stabilizes p53 with the hope that these insights may be applied to develop targeted therapeutic strategies for cancer treatment.