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

• The p38 group of kinases belongs to the mitogen-activated protein (MAP) kinase superfamily with structural and functional characteristics distinguishable from those of the ERK, JNK (SAPK), and BMK (ERK5) kinases. Although there is a high degree of similarity among members of the p38 group in terms of structure and activation, each member appears to have a unique function. Here we show that activation of p38-? (also known as ERK6 or SAPK3), but not the other p38 isoforms, is required for ?-irradiation- induced G2 arrest. Activation of the MKK6-p38? cascade is sufficient to induce G2 arrest in cells, and expression of dominant negative alleles of MKK6 or p38? allows cells to escape the DNA damage-induce G2 delay. Activation of p38? 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 ? irradiation leads to the activation of MKK6, p38?, and Cds1 and that activation of both MKK6 and p38? is essential for the proper regulation of the G2 checkpoint in mammalian cells.

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