The fact that NF-kappaB is activated in response to stress (24) and that there is a conserved kappaB site in the PPM1D promoter region (Figure 1) suggested that NF-kappaB regulates levels of PPM1D transcription, which was validated by our group (5). Inhibition of NF-kappaB chemically or by siRNA directed to the p65 subunit reduced basal levels of Wip1 mRNA and protein in MCF-7 breast cancer cells, which indicates that NF-kappaB is responsible, at least in part, for basal Wip1 expression. Reporter constructs and ChIP assays showed that the kappaB site is required for full basal PPM1D promoter activity and that p65 binds directly to the PPM1D promoter region (5). Additionally, as shown in Figure 2, stimulation with lipopolysaccharide (LPS) or the cytokine Tumor Necrosis Factor-alpha (TNF-alpha), both well-known NF-kappaB activators, increased PPM1D mRNA levels (5, 6). These studies showed that constitutively active NF-kappaB in cancer cells (such as in MCF-7 breast cancer cells) or cytokine-activated NF-kappaB induced Wip1 expression. However, as NF-kappaB is activated in response to many types of stress including genotoxic stress, NF-kappaB may regulate Wip1 expression after other types of stress as well.
