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 ΔNp63α, the function of which is not fully understood. ΔNp63α 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 ΔNp63α expression in response to chemotherapeutic agents or tumor necrosis factor-α. We found that ΔNp63α interacts with IκB kinase (IKK), a multisubunit protein kinase that consists of two catalytic subunits, IKKκ and IKKβ, and a regulatory subunit, IKKγ. The IKKβ kinase promotes ubiquitin-mediated proteasomal degradation of ΔNp63α, whereas a kinasedeficient mutant IKKβ-K44A fails to do so. Cytokine- or chemotherapy-induced stimulation of IKKβ caused degradation of ΔNp63α and augmented transactivation of p53 family-induced genes involved in the cellular response to DNA damage. Conversely, IKKβ inhibition attenuated cytokine- or chemotherapy-induced degradation of ΔNp63α. Our findings show that IKKβ plays an essential role in regulating ΔNp63α in response to extrinsic stimuli. IKK activation represents one mechanism by which levels of ΔNp63α can be reduced, thereby rendering cells susceptible to cell death in the face of cellular stress or DNA damage.