The SWIB/MDM2 motif of UBE4B activates the p53 pathway

The tumor suppressor p53 plays a critical role in cancer pathogenesis, and regulation of p53 expression is essential for maintaining normal cell growth. UBE4B is an E3/E4 ubiquitin ligase involved in a negative-feedback loop with p53. UBE4B is required for Hdm2-mediated p53 polyubiquitination and degradation. Thus, targeting the p53-UBE4B interactions is a promising anticancer strategy for cancer therapy. In this study, we confirm that while the UBE4B U box does not bind to p53, it is essential for the degradation of p53 and acts in a dominantnegative manner, thereby stabilizing p53. C-terminal UBE4B mutants lose their ability to degrade p53. Notably, we identified one SWIB/Hdm2 motif of UBE4B that is vital for p53 binding. Furthermore, the novel UBE4B peptide activates p53 functions, including p53-dependent transactivation and growth inhibition, by blocking the p53-UBE4B interactions. Our findings indicate that targeting the p53-UBE4B interaction presents a novel approach for p53 activation therapy in cancer.

Automated summary

The tumor suppressor p53 is crucial in cancer pathogenesis and maintaining normal cell growth by regulating p53 expression. UBE4B is an E3/E4 ubiquitin ligase involved in a negative-feedback loop with p53, playing a role in its degradation. Therefore, targeting the p53-UBE4B interaction is a promising strategy for anticancer therapy. In this study, we found that the UBE4B U box does not bind to p53 but is essential for its degradation. Certain mutants of UBE4B lose their ability to degrade p53, and a SWIB/Hdm2 motif of UBE4B is vital for p53 binding. Furthermore, a novel UBE4B peptide activates p53 functions by blocking the p53-UBE4B interaction, suggesting a new approach for p53 activation therapy in cancer.