U-box-type ubiquitin E4 ligase, UFD2a attenuates cisplatin mediated degradation of ΔNp63α

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 down regulated in response to several DNA damaging agents, including cisplatin. But little is understood about the post-translational protein stability of Delta Np63 alpha. In this present study we demonstrate for the first time that Delta Np63 alpha physically interacts with U-box-type E4 ubiquitin ligase UFD2a. UFD2a stabilizes Delta Np63 alpha, and ubiquitylation of Delta Np63 alpha is attenuated by UFD2a both in the presence and absence of cisplatin. Ectopic expression of UFD2a increased the half-life of Delta Np63 alpha in association with a significant enhancement of the repressive transcriptional activity of Delta Np63 alpha. Downregulation of endogenous UFD2a by RNAi resulted in degradation of Delta Np63 alpha. Taken together, our current study provides an insight onto the regulation of Delta Np63 alpha protein levels in response to cisplatin and also suggests that UFD2a might play an important role in the regulation of cisplatin mediated cell death by p63.