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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 de...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society of Gene & Cell Therapy
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9971181/ https://www.ncbi.nlm.nih.gov/pubmed/36865087 http://dx.doi.org/10.1016/j.omtn.2023.02.002 |
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author | Wu, H. Helena Leng, Sarah Abuetabh, Yasser Sergi, Consolato Eisenstat, David D. Leng, Roger |
author_facet | Wu, H. Helena Leng, Sarah Abuetabh, Yasser Sergi, Consolato Eisenstat, David D. Leng, Roger |
author_sort | Wu, H. Helena |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9971181 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Society of Gene & Cell Therapy |
record_format | MEDLINE/PubMed |
spelling | pubmed-99711812023-03-01 The SWIB/MDM2 motif of UBE4B activates the p53 pathway Wu, H. Helena Leng, Sarah Abuetabh, Yasser Sergi, Consolato Eisenstat, David D. Leng, Roger Mol Ther Nucleic Acids Original Article 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. American Society of Gene & Cell Therapy 2023-02-04 /pmc/articles/PMC9971181/ /pubmed/36865087 http://dx.doi.org/10.1016/j.omtn.2023.02.002 Text en © 2023 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Original Article Wu, H. Helena Leng, Sarah Abuetabh, Yasser Sergi, Consolato Eisenstat, David D. Leng, Roger The SWIB/MDM2 motif of UBE4B activates the p53 pathway |
title | The SWIB/MDM2 motif of UBE4B activates the p53 pathway |
title_full | The SWIB/MDM2 motif of UBE4B activates the p53 pathway |
title_fullStr | The SWIB/MDM2 motif of UBE4B activates the p53 pathway |
title_full_unstemmed | The SWIB/MDM2 motif of UBE4B activates the p53 pathway |
title_short | The SWIB/MDM2 motif of UBE4B activates the p53 pathway |
title_sort | swib/mdm2 motif of ube4b activates the p53 pathway |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9971181/ https://www.ncbi.nlm.nih.gov/pubmed/36865087 http://dx.doi.org/10.1016/j.omtn.2023.02.002 |
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