Another mechanism by which PPM1D mRNA stability is affected is through BRCA-IRIS. Unlike the tumor suppressor BRCA1, which is derived from the same locus, BRCA-IRIS is oncogenic and promotes cell cycle progression, cell survival and proliferation (40–42). In contrast to destabilization by miR-16, BRCA-IRIS enhances PPM1D mRNA stability. It does so through the enhancement of the RNA binding protein HuR, which stabilizes mRNA by binding to the 3′ untranslated region (43, 44). It was shown that, in breast cancer cells, overexpression or knock down of BRCA-IRIS leads, respectively, to increased or decreased Wip1 expression, as determined by immunoblotting and RT-PCR. Immunoblot analysis showed that BRCA-IRIS stabilized HuR and increased its cytoplasmic expression. This occurs presumably through NF-kappaB, since NF-kappaB is known to regulate HuR expression and overexpression of BRCA-IRIS leads to nuclear localization of the p65 subunit of NF-kappaB. HuR then binds to Wip1 mRNA to prevent its degradation, which leads to an enhanced Wip1 expression (Figure 3) (43). As BRCA1-IRIS, HuR, and Wip1 are all induced after UV radiation exposure, it is thought that this mechanism is activated after
