Antioxidants as well as oxidants activate c-fos via Ras-dependent activation of extracellular-signal-regulated kinase 2 and Elk-1

Abstract

Intracellular reactive oxygen intermediate (ROI) levels play an important role in numerous physiological and pathophysiological conditions. Apart from causing oxidative stress and damage, ROI changes differentially activate gene expression. However the proto-oncogene encoding the AP-1 transcription factor subunit c-Fos is induced by both prooxidants and antioxidants. Here, the transcription factor Elk-1 is identified as being responsible for c-fos serum response element (SRE) induction in response to changes in the cellular redox status induced by treatment with either the oxidant H2O2 or various structurally unrelated antioxidants. A temporal correlation is observed between changes in the phosphorylation status of Elk-l and the activation of the mitogen-activated protein kinase 2 (ERK2) in response to cellular redox changes. Correspondingly, the transcriptional response of the SRE to redox fluctuations is attenuated upon mutation of critical ERK2 target residues within the Elk-1 transactivation domain to alanine. Signals elicited by antagonistic intracellular redox changes converge at or above the level of Ras or an effector of Ras, leading to similar activation of c-fos transcription, since an [N17]Ras mutant interfered with redox signaling. Hence components of signaling pathways are revealed to be shared by mitogenic and redox-dependent stimuli.