Involvement of the MKK6-p38 gamma cascade in gamma-radiation-induced cell cycle arrest

The p38 group of kinases belongs to the mitogen-activated protein (MAP) kin ase superfamily with structural and functional characteristics distinguisha ble from those of the ERK, JNK (SAPK), and BMK (ERK5) kinases. Although the re is a high degree of similarity among members of the p38 group in terms o f structure and activation, each member appears to have a unique function. Here we show that activation of p38 gamma (also known as ERK6 or SAPK3), bu t not the other p38 isoforms, is required for gamma-irradiation-induced G(2 ) arrest. Activation of the MKK6-p38 gamma cascade is sufficient to induce G(2) arrest in cells, and expression of dominant negative alleles of MKK6 o r p38 gamma allows cells to escape the DNA damage-induce G(2) delay. Activa tion of p38 gamma is dependent on ATM and leads to activation of Cds1 (also known as Chk2). These data suggest a model in which activation of ATM by g amma irradiation leads to the activation of MKK6, p38 gamma, and Cds1 and t hat activation of both MKK6 and p38 gamma is essential for the proper regul ation of the G(2) checkpoint in mammalian cells.