Regulation of p53 Family Member Isoform ΔNp63α by the Nuclear Factor-κB Targeting Kinase IκB Kinase β

The p53 family gene p63 plays an instrumental role in cellular stress responses including responses to DNA damage. In addition to encoding a full-length transcriptional activator, p63 also encodes several dominant inhibitory isoforms including the isoform Delta Np63 alpha, the function of which is not fully understood. Delta Np63 alpha is degraded in response to DNA damage, thereby enabling an effective cellular response to genotoxic agents. Here, we identify a key molecular mechanism underlying regulation of Delta Np63 alpha expression in response to chemotherapeutic agents or tumor necrosis factor-alpha. We found that Delta Np63 alpha interacts with I kappa B kinase (IKK), a multisubunit protein kinase that consists of two catalytic subunits, IKK alpha and IKK beta, and a regulatory subunit, IKK gamma. The IKK beta kinase promotes ubiquitin-mediated proteasomal degradation of Delta Np63 alpha, whereas a kinase-deficient mutant IKK beta-K44A fails to do so. Cytokine- or chemotherapy-induced stimulation of IKK beta caused degradation of Delta Np63 alpha and augmented transactivation of p53 family-induced genes involved in the cellular response to DNA damage. Conversely, IKK beta inhibition attenuated cytokine- or chemotherapy-induced degradation of Delta Np63 alpha. Our findings show that IKK beta plays an essential role in regulating Delta Np63 alpha in response to extrinsic stimuli. IKK activation represents one mechanism by which levels of Delta Np63 alpha can be reduced, thereby rendering cells susceptible to cell death in the face of cellular stress or DNA damage. Cancer Res; 70(4); 1419-29. (C) 2010 AACR.