The SWIB/MDM2 motif of UBE4B activates the p53 pathway

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

Molecular Therapy: Nucleic Acids (Mar 2023)

The SWIB/MDM2 motif of UBE4B activates the p53 pathway

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

Affiliations

H. Helena Wu: 370 Heritage Medical Research Center, Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB T6G 2S2, Canada
Sarah Leng: Department of Laboratory Medicine and Pathology (5B4. 09), University of Alberta, Edmonton, AB T6G 2B7, Canada
Yasser Abuetabh: 370 Heritage Medical Research Center, Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB T6G 2S2, Canada
Consolato Sergi: Department of Laboratory Medicine and Pathology (5B4. 09), University of Alberta, Edmonton, AB T6G 2B7, Canada; Division of Anatomical Pathology, Children’s Hospital of Eastern Ontario (CHEO), University of Ottawa, 401 Smyth Road, Ottawa, ON K1H 8L1, Canada
David D. Eisenstat: Department of Oncology, Cross Cancer Institute, 11560 University Avenue, University of Alberta, Edmonton, AB T6G 1Z2, Canada; Department of Pediatrics, University of Alberta, 11405 - 87 Avenue, Edmonton, AB T6G 1C9, Canada; Department of Medical Genetics, University of Alberta, 8613 114 Street, Edmonton, AB T6G 2H7, Canada; Murdoch Children’s Research Institute, Department of Paediatrics, University of Melbourne, 50 Flemington Road, Parkville, VIC 3052, Australia
Roger Leng: 370 Heritage Medical Research Center, Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB T6G 2S2, Canada; Corresponding author: Roger Leng, 370 Heritage Medical Research Center, Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB T6G 2S2, Canada.

Journal volume & issue: Vol. 31
pp. 466 – 481

Abstract

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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.

Published in Molecular Therapy: Nucleic Acids

ISSN: 2162-2531 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: https://www.cell.com/molecular-therapy-family/nucleic-acids/latest-content

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