Repression of Dmp1 and Arf transcription by anthracyclins:: critical roles of the NF-κB subunit p65

Both genotoxic and oncogenic stress activates the nuclear factor-kappa B (NF-kappa B) and p53 proteins however the p53 activity is antagonized by NF-kappa B signaling. Dmp1 is a Myb-like transcription factor that activates the Arf-p53 pathway. The Dmp1 promoter was activated by a classical NF-kappa B activator tumor necrosis factor a but repressed by treatment of cells with non classical NF-kappa B activators anthracyclins and UV-C. p65 and other subsets of NF-kappa B proteins were bound to the Dmp1 promoter following anthracyclin/UV-C treatment of rodent. broblasts. This resulted in the downregulation of Dmp1 mRNA and protein. Repression of the Dmp1 transcription by anthracyclins depended on the unique NF-kappa B site on the promoter. Downregulation of p65 significantly attenuated the repression of the Dmp1 promoter by anthracyclins/UV-C. The amount of Dmp1 bound to the Arf promoter decreased significantly upon anthracyclin treatment this in turn downregulated the Arf levels. Repression of the Arf promoter by p65 or anthracyclins depended on Dmp1 which was significantly attenuated in Dmp1(-/-) cells. Both Dmp1(-/-) and Arf(-/-) cells showed resistance to anthracyclin-induced cell death compared to wild-type cells non-immortalized p65-knockdown cells were much more sensitive. Thus the Dmp1-Arf pathway is repressed by p65 in response to genotoxic stress which implicates a novel mechanism of p53 inactivation by NF-kappa B.