Abstract
BackgroundThe ubiquitously expressed POU homeodomain protein Oct-1 serves as a sensor for stress induced by irradiation. We found recently that in pancreatic and intestinal endocrine cells, Oct-1 also functions as a sensor for cyclic AMP (cAMP). The caudal homeobox gene Cdx-2 is a transactivator of proglucagon (gcg) and pro-insulin genes. Oct-1 binds to Cdx-2 promoter and represses its expression. cAMP elevation leads to increased nuclear exclusion of Oct-1, associated with reduced recruitment of nuclear co-repressors to the Cdx-2 promoter and increased Cdx-2 expression.ResultsWe show in this study that inducing oxidative stress by hydrogen peroxide (H2O2) increased nuclear Oct-1 content in both pancreatic α and β cell lines, as well as in a battery of other cells. This increase was then attributed to accelerated nuclear import of Oct-1, assessed by Fluorescence Recovery After Photobleaching (FRAP) using green fluorescence protein (EGFP) tagged Oct-1 molecule. H2O2 treatment was then shown to stimulate the activities of DNA-dependent protein kinase (DNA-PK) and c-jun N-terminal kinase (JNK). Finally, increased Oct-1 nuclear content upon H2O2 treatment in a pancreatic α cell line was associated with reduced Cdx-2 and gcg mRNA expression.ConclusionThese observations suggest that Oct-1 functions as a sensor for both metabolic and stress/survival signaling pathways via altering its nuclear-cytoplasmic shuttling.
Highlights
The ubiquitously expressed POU homeodomain protein octamer transcription factor-1 (Oct-1) serves as a sensor for stress induced by irradiation
hydrogen peroxide (H2O2) treatment increases nuclear Oct-1 levels Given that oxidative stress in pancreatic islet cells is a major contributor of islet cell damage and subsequent diabetic hyperglycemia, and that Oct-1 is a known sensor for radiation mediated and other types of stress, we assessed whether oxidative stress affects Oct-1 subcellular distribution by Western blotting
We have investigated whether oxidative stress would affect Oct-1 nuclear content in other cell lineages
Summary
The ubiquitously expressed POU homeodomain protein Oct-1 serves as a sensor for stress induced by irradiation. The protein in this family typically contains a bipartite DNA binding domain, in which two sub-domains are covalently connected by a flexible linker These two sub-domains normally recognize DNA through major elevation reduced the binding of Oct-1 to Cdx-2 promoter and the recruitment of nuclear co-repressors, including silencing mediator of retinoid and thyroid hormone receptors (SMRT) and histone deacetylase 1 (HDAC1)[12]. These observations suggest that Oct-1 functions as a transcriptional repressor for a set of target genes, while cAMP elevation in response to the stimulation by peptide hormones leads to the release of the repressive effect
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