The SWIB/MDM2 motif of UBE4B activates the p53 pathway

H Helena Wu; Sarah Leng; Yasser Abuetabh; Consolato Sergi; David D Eisenstat; Roger Leng

doi:10.1016/j.omtn.2023.02.002

The SWIB/MDM2 motif of UBE4B activates the p53 pathway

Mol Ther Nucleic Acids. 2023 Feb 4:31:466-481. doi: 10.1016/j.omtn.2023.02.002. eCollection 2023 Mar 14.

Authors

H Helena Wu¹, Sarah Leng², Yasser Abuetabh¹, Consolato Sergi^{2

3}, David D Eisenstat^{4

5

6

7}, Roger Leng¹

Affiliations

¹ 370 Heritage Medical Research Center, Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB T6G 2S2, Canada.
² Department of Laboratory Medicine and Pathology (5B4. 09), University of Alberta, Edmonton, AB T6G 2B7, Canada.
³ Division of Anatomical Pathology, Children's Hospital of Eastern Ontario (CHEO), University of Ottawa, 401 Smyth Road, Ottawa, ON K1H 8L1, Canada.
⁴ Department of Oncology, Cross Cancer Institute, 11560 University Avenue, University of Alberta, Edmonton, AB T6G 1Z2, Canada.
⁵ Department of Pediatrics, University of Alberta, 11405 - 87 Avenue, Edmonton, AB T6G 1C9, Canada.
⁶ Department of Medical Genetics, University of Alberta, 8613 114 Street, Edmonton, AB T6G 2H7, Canada.
⁷ Murdoch Children's Research Institute, Department of Paediatrics, University of Melbourne, 50 Flemington Road, Parkville, VIC 3052, Australia.

Abstract

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.

Keywords: G1 arrest; MT: Oligonucleotides: Therapies and Applications; UBE4B; apoptosis; p53; peptide.