Mitogen-activated protein kinase kinase 2 activation is essential for progression through the G(2)/M checkpoint arrest in cells exposed to ionizing radiation

An increasing body of evidence suggests that mitogen-induced activation of the RAF/ERK signaling pathway is functionally separate from the stress-indu ced activation of the SEK/JNK/p38 signaling pathway. In general, stress sti muli strongly activate the p38s and the JNKs while only weakly activating E RK1 and ERK2. However, a number of independent groups have now shown that t he RAF/ERK signaling pathway is strongly activated by ionizing radiation. I n this work, we examine this paradox. We show that both mitogen-activated p rotein (MAP) kinase kinase 1 (MEK1) and MAP kinase kinase 2 (MEK2) are acti vated by ionizing radiation. Blockage of this activation through the use of dominant negative MEK2 increases sensitivity of the cell to ionizing radia tion and decreases the ability of a cell to recover from the G(2)/M cell cy cle checkpoint arrest. Blocking MEK2 activation does not affect double-stra nd DNA break repair, however, Although MEK1 is activated to a lesser extent by ionizing radiation, expression of a dominant negative MEK1 does not aff ect radiation sensitivity of the cell, the G(2)/M checkpoint of the cell, o r double-strand break repair. Because ionizing radiation leads to a differe nt cell cycle arrest (G(2)/M arrest) than that typically seen with other st ress stimuli, and because we have shown that MEK2 can affect G(2)/M checkpo int kinetics, these results provide an explanation for the observation that the MEKs can be strongly activated by ionizing radiation and only weakly a ctivated by other stressful stimuli.