p53- and Mdm2-independent repression of NF-κB transactivation by the ARF tumor suppressor

One mechanism by which a cell affords protection from the transforming effects of oncogenes is via the action of the tumor suppressor, ARF, which activates p53 by inactivating Mdm2. Many oncogenes have also been shown to activate the transcription factor NF-kappaB, which can contribute toward the malignant phenotype in many ways, including an ability to antagonize p53. Here we find that ARF inhibits NF-kappaB function and its antiapoptotic activity independent of Mdm2 and p53. ARF represses the transcriptional activation domain of the NF-kappaB family member ReIA by inducing its association with the histone deacetylase, HDAC1. Further, we show that the response of NF-kappaB to the oncogene Bcr-Abl is determined by the ARF status of the cell. These results reveal an important function of ARF that can regulate the NF-kappaB response to oncogene activation.