CHOP transcription factor phosphorylation by casein kinase 2 inhibits transcriptional activation.

The CAAT/enhancer binding protein homologous transcription factor CHOP, also known as GADD153, is involved in DNA damage, growth arrest, and the induction of apoptosis after endoplasmic reticulum stress and nutrient deprivation. CHOP dimerizes with and inhibits the binding of C/EBP-related transcription factors to their consensus DNA target sequences and also forms novel complexes with other transcriptional proteins (e.g. c-Jun, c-Fos). The transcriptional activation of these complexes is modified by their phosphorylation. Phosphorylation of CHOP at serine 79 and serine 81 by p38-MAP kinase enhances its transcriptional activity. Here we show that an interactive association between CHOP and casein kinase II (CK2) results in the phosphorylation of its amino-terminal transactivation domain. Mapping of the functional domains of CHOP indicates that the region in CHOP required for association with CK2 differs from that required for its phosphorylation. Th binding of CK2 to CHOP requires only the carboxylterminal bZip domain of CHOP, whereas phosphorylation involves residues located in the amino-terminal domain. The presence of the bZip domain, however, facilitates the phosphorylation of CHOP. Analyses of the effect of point mutations of CHOP on its transcriptional activity and the effect of specific inhibitors of CK2 lead us to conclude that CK2-mediated phosphorylation of CHOP inhibits its transcriptional activity. Our findings suggest that inhibition of the proapoptotic functions of CHOP by CK2 may be a mechanism by which CK2 prevents apoptosis and promotes cellular proliferation.