A conserved cyclic AMP response element (CRE) was identified in the human and mouse PPM1D promoter regions (Figure 1), and the binding of the CRE binding protein (CREB) to the PPM1D promoter in HEK 293 cells and human hepatocytes was determined in a genome-wide association study (22, 23), suggesting that CREB regulates the expression of Wip1. The positive regulation of PPM1D transcription by CREB was confirmed by reporter assays and ChIP experiments (19). In contrast to p53 regulation of Wip1, which occurs in response to genotoxic stress, CREB also regulates basal PPM1D transcription in cultured cells (Figure 2). In the absence of exogenous stress, a luciferase reporter construct with a mutated CRE in the PPM1D promoter showed reduced luciferase activity levels (by over 40%) compared to the wild type PPM1D promoter in colon cancer HCT-116 cells. Additionally, ChIP analysis in HCT-116 wild type and p53−/− cells revealed that CREB was bound to the PPM1D promoter region in the absence of stress and independent of the presence of p53, which further supports a role of CREB in basal PPM1D transcriptional regulation
