Regulation of ΔNp63α by NFκB

Delta Np63 alpha, the dominant negative isoform of the p63 family is an essential survival factor in head and neck squamous cell carcinoma. This isoform has been shown to be downregulated in response to several DNA damaging agents, thereby enabling an effective cellular response to genotoxic agents. Here, we identify a key molecular mechanism underlying the regulation of Delta Np63 alpha expression in response to extrinsic stimuli, such as chemotherapeutic agents. We show that Delta Np63 alpha interacts with NF kappa B in presence of cisplatin. We find that NF kappa B promotes ubiquitin-mediated proteasomal degradation of Delta Np63 alpha. Chemotherapy-induced stimulation of NF kappa B leads to degradation of Delta Np63 alpha and augments trans-activation of p53 family-induced genes involved in the cellular response to DNA damage. Conversely, inhibition of NF kappa B with siRNA-mediated silencing NF kappa B expression attenuates chemotherapy induced degradation of Delta Np63 alpha. These data demonstrate that NF kappa B plays an essential role in regulating Delta Np63 alpha in response to extrinsic stimuli. Our findings suggest that the activation of NF kappa B may be a mechanism by which levels of Delta Np63 alpha are reduced, thereby rendering the cells susceptible to cell death in the face of cellular stress or DNA damage.