In cardiac myoblasts, cellular redox regulates FosB and Fra-1 through multiple cis-regulatory modules.

Depending on the dose, norepineprine (NE) can induce hypertrophy or apoptosis in cardiac myocytes. Reactive oxygen species play a key role in mediating both responses, but the mechanisms are not understood as yet. Earlier we demonstrated that the two pathways are marked by the differential induction of FosB and Fra-1, two members of the AP-1 family of transcription factors. We now demonstrate that NE induces both fosB and fra-1 at the transcriptional level. Catalase and MnTMPyP (a superoxide dismutase mimetic) suppress their activation by NE. In contrast, in cells without NE treatment, MnTMPyP upregulates their expression, whereas catalase inhibits it. Thus, regulation of fosB and fra-1 by is context specific. To delineate the mechanisms, the 1493- and 2689-bp upstream regions of the fosB and fra-1 genes were cloned into the luciferase vector and assayed for transient expression. Catalase and MnTMPyP regulated both promoters the same as their endogenous counterparts in NE-treated and untreated cells. Deletion, mutation, and ChIP analyses suggested that multiple cis-elements including SP-1, CEBP, and AP-1 in the fosB promoter make discrete contributions to mediating the redox response. A gel mobility-shift-based oxidation-reduction assay suggested that, whereas SP-1 is a direct sensor of cellular redox state, CEBP is not. This study suggests that multiple redox signals generate gene-specific modules affecting their expression.

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