Oct-1 functions as a sensor for metabolic and stress signals

Abstract

Oct-1 should not be simply considered as a repressor for a cluster of genes. Instead, it is a sensor for both metabolic and stress/survival signaling pathways. Indeed, a recent study shows that Oct-1 mediates the effect of oxidized LDL (oxLDL) in repressing the expression of vascular cytochrome P450 (CYP) monooxygenases.12 In human coronary arterial endothelial cells, knockdown of Oct-1 expression prevented oxLDL-mediated silencing of CYP expression.12 Furthermore, inhibition of oxLDL receptor (LOX-1) attenuated oxLDL-mediated endothelial DNA damage, Oct-1 DNA binding, and reversed impaired production of endothelial-derived hyperpolarization factor (EDHF).12 Therefore, Oct-1 activation in response to the signal of oxidative stress is among the pathological entity in metabolic dysfunction, 12 and attenuating the function of Oct-1 improves the dysfunction. As shown in Figure 1, the ubiquitously expressed transcription factor Oct-1 usually functions as a repressor. In response to the stimulation by a peptide hormone, such as GLP-1 or insulin, Oct-1 is phosphorylated at certain Thr positions, possibly involving Epac and ERK activation. This leads to Oct-1 nuclear exclusion and increased Oct-1 target gene expression (Fig. 1A). In response to metabolic or oxidative stress, DNA-PK activity increases. This results in Oct-1 phosphorylation at the sites other than that by Epac-ERK signaling. This type of phosphorylation will make Oct-1 imported into the nuclei, followed by increased recruitment of nuclear co-repressors to the promoter region, silencing its target gene expression (Fig. 1B). To further appreciate the role of Oct-1 in metabolic homeostasis, it is essential to identify phosphorylation sites by various metabolic and stress/survival signals. © 2010 Landes Bioscience.