Hydrogen peroxide stimulates nuclear import of the POU homeodomain protein Oct-1 and its repressive effect on the expression of Cdx-2
1 Div. of Cell and Molecular Biology, Toronto General Research Institute, University Health Network, 10-354 Toronto Medical Discovery Tower, The MaRS Building, 101 College St., Toronto, Ontario, M5G 1L7, Canada
2 Dept. of Laboratory Medicine and Pathobiology, University of Toronto, 1 King's College Circle, Toronto, Ontario, M5 S 1A8, Canada
3 Dept. of Medicine, University of Toronto, 200 Elizabeth Street, Toronto, Ontario, M5G 2C4, Canada
4 Department of Physiology, University of Toronto, 1 King's College Circle, Toronto, Ontario, M5 S 1A8, Canada
5 Dept. of Nutrition, School of Public Health, Sun Yat-Sen University, 74 2nd Zhongshan Road, Guangzhou, Guangdong Province, 510080, PR China
BMC Cell Biology 2010, 11:56 doi:10.1186/1471-2121-11-56Published: 16 July 2010
The 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.
We 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.
These observations suggest that Oct-1 functions as a sensor for both metabolic and stress/survival signaling pathways via altering its nuclear-cytoplasmic shuttling.