Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 280, Issue 11, Pages 9786-9795Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M414006200
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- NIGMS NIH HHS [S06-GM08037-32] Funding Source: Medline
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Very little is known regarding molecular mechanism(s) underlying transcriptional regulation of any G-protein gene despite the importance of G-protein expression in modulating cellular processes. Here we show that phorbol myristate acetate (PMA) and tert-butylhydroquinone (tBHQ), which induce oxidative stress in cells, up-regulate transcription of G alpha(i2) in K562 cells. Redox-sensing chemicals abrogated this transcriptional effect. A dominant negative I-kappa B double mutant (S32A/S36A) suppressed PMA-induced transcription by 54-62%, suggesting involvement of nuclear factor-kappa B (NF-kappa B). SN50, a cell-permeable peptide that inhibits nuclear import of stress-responsive transcription factors (such as NF-kappa B), inhibited PMA- and tBHQ-induced transcription. Deletion of an NF-kappa B-binding motif that maps at +10/+19 in the promoter resulted in 55-60% suppression of PMA- induced transcription, and 81% suppression of tBHQ-induced transcription. Mutation of an antioxidant response element ( ARE) that maps at -84/-76 in the promoter resulted in 51 and 86% decrease in PMA- and tBHQ-induced transcription, respectively. In electrophoretic mobility shift assays, this element formed complexes with the transcription factors NF-E2p45 and Nrf2 that are prototypic for binding to the ARE, as well as with c-Fos, which can also interact with the ARE. Chromatin immunoprecipitation analysis demonstrated recruitment of these transcription factors to the promoter. Exogenously transfected Nrf2 transactivated the G alpha(i2) gene promoter; the cytoskeleton-associated protein, Keap1, abrogated this effect. Taken together, the present studies reveal that transcription factors that bind NF-kappa B and/or antioxidant response elements play an activating role in the transcription of the human G alpha(i2) gene.
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