Wu H Helena, Leng Sarah, Abuetabh Yasser, Sergi Consolato, Eisenstat David D, Leng Roger
370 Heritage Medical Research Center, Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB T6G 2S2, Canada.
Department of Laboratory Medicine and Pathology (5B4. 09), University of Alberta, Edmonton, AB T6G 2B7, Canada.
Mol Ther Nucleic Acids. 2023 Feb 4;31:466-481. doi: 10.1016/j.omtn.2023.02.002. eCollection 2023 Mar 14.
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 dominant-negative 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.
肿瘤抑制因子p53在癌症发病机制中起关键作用，p53表达的调控对于维持正常细胞生长至关重要。UBE4B是一种E3/E4泛素连接酶，参与与p53的负反馈回路。UBE4B是Hdm2介导的p53多聚泛素化和降解所必需的。因此，靶向p53-UBE4B相互作用是一种有前景的癌症治疗抗癌策略。在本研究中，我们证实虽然UBE4B的U盒不与p53结合，但它对于p53的降解至关重要，并以显性负性方式发挥作用，从而稳定p53。UBE4B的C末端突变体失去了降解p53的能力。值得注意的是，我们鉴定出UBE4B的一个SWIB/Hdm2基序对p53结合至关重要。此外，新型UBE4B肽通过阻断p53-UBE4B相互作用激活p53功能，包括p53依赖性反式激活和生长抑制。我们的研究结果表明，靶向p53-UBE4B相互作用为癌症中的p53激活疗法提供了一种新方法。
