Dual potential of extracellular signal-regulated kinase for the control of cell survival.

Extracellular signal-regulated kinase (ERK) controls cell proliferation positively or negatively depending on the cellular contexts in which ERK is activated. In this report, we address differential roles of transient and constitutive activation of ERK in cell survival. Under a basal culture condition, mesangial cells showed modest, sustained ERK activity. The activity of ERK was transiently upregulated (15-60 min) in response to hydrogen peroxide (H(2)O(2)). The cells exposed to H(2)O(2) exhibited shrinkage of the cytoplasm, condensation/fragmentation of nuclei and DNA ladder typical of apoptosis. Inhibition of the transient ERK activation by MEK inhibitor PD098059 attenuated the H(2)O(2)-induced apoptosis. In contrast, inactivation of the constitutive ERK by PD098059 induced morphologic and biochemical features of apoptosis under the unstimulated, basal culture condition. Consistently, transfection with dominant-negative mutants of ERK1 and ERK2 inhibited H(2)O(2)-induced apoptosis, whereas it facilitated apoptosis of unstimulated cells. These results suggested the novel, dual potential of ERK for the regulation of cell survival. Transient upregulation of ERK participates in the induction of apoptosis, whereas basal, constitutive activity of ERK is required for the maintenance of cell survival. Copyright 1999 Academic Press.