Antioxidant-induced Nuclear Translocation of CCAAT/Enhancer-binding Protein β

Abstract

Alterations in intracellular oxidative status activate several signal transduction pathways resulting in dis- tinct patterns of gene expression. Treatment of colorec- tal cancer cells with antioxidants can lead to apoptosis by induction of p21 through a mechanism involving CCAAT/enhancer-binding protein ? (C/EBP ). Herein, ? we demonstrate that the antioxidant pyrrolidinedithio- carbamate activates cAMP-dependent protein kinase (PKA) in a colorectal cancer cell line DKO-1. Activation of PKA phosphorylates Ser299 within C/EBP ? , which is essential for protein translocation to the nucleus. Phar- macological inhibition of PKA and mutation of Ser299 to alanine blocks C/EBP ? nuclear translocation and induc- tion of p21. Our results indicate that a cAMP-dependent phosphorylation of C/EBP ? at Ser299 is critical for nu- clear translocation of this protein and its subsequent transactivation of genes in response to antioxidant treatment.