Cargando…
The Dual Roles of MAGE-C2 in p53 Ubiquitination and Cell Proliferation Through E3 Ligases MDM2 and TRIM28
The tumor suppressor p53 is critical for the maintenance of genome stability and protection against tumor malignant transformation, and its homeostasis is usually regulated by ubiquitination. MDM2 is a major E3 ligase of p53 ubiquitination, and its activity is enhanced by TRIM28. TRIM28 also indepen...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9344466/ https://www.ncbi.nlm.nih.gov/pubmed/35927984 http://dx.doi.org/10.3389/fcell.2022.922675 |
_version_ | 1784761226865147904 |
---|---|
author | Liu, Yunshan Cao, Beibei Hu, Liqiao Ye, Jingjing Tian, Wei He, Xiaojing |
author_facet | Liu, Yunshan Cao, Beibei Hu, Liqiao Ye, Jingjing Tian, Wei He, Xiaojing |
author_sort | Liu, Yunshan |
collection | PubMed |
description | The tumor suppressor p53 is critical for the maintenance of genome stability and protection against tumor malignant transformation, and its homeostasis is usually regulated by ubiquitination. MDM2 is a major E3 ligase of p53 ubiquitination, and its activity is enhanced by TRIM28. TRIM28 also independently ubiquitinates p53 as an E3 ligase activated by MAGE-C2. Moreover, MAGE-C2 is highly expressed in various cancers, but the detailed mechanisms of MAGE-C2 involved in MDM2/TRIM28-mediated p53 ubiquitination remain unknown. Here, we found that MAGE-C2 directly interacts with MDM2 through its conserved MHD domain to inhibit the activity of MDM2 on p53 ubiquitination. Furthermore, TRIM28 acts as an MAGE-C2 binding partner and directly competes with MAGE-C2 for MDM2 interaction, thus releasing the inhibitory role of MAGE-C2 and promoting p53 ubiquitination. MAGE-C2 suppresses cell proliferation in TRIM28-deficient cells, but the overexpression of TRIM28 antagonizes the inhibitory role of MAGE-C2 and accumulates p53 ubiquitination to promote cell proliferation. This study clarified the molecular link of MAGE-C2 in two major E3 systems MDM2 and TRIM28 on p53 ubiquitination. Our results revealed the molecular function of how MAGE-C2 and TRIM28 contribute to p53 ubiquitination and cell proliferation, in which MAGE-C2 acts as a potential inhibitor of MDM2 and TRIM28 is a vital regulator for MAGE-C2 function in p53 protein level and cell proliferation. This work would be helpful to understand the regulation mechanism of tumor suppressor p53. |
format | Online Article Text |
id | pubmed-9344466 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-93444662022-08-03 The Dual Roles of MAGE-C2 in p53 Ubiquitination and Cell Proliferation Through E3 Ligases MDM2 and TRIM28 Liu, Yunshan Cao, Beibei Hu, Liqiao Ye, Jingjing Tian, Wei He, Xiaojing Front Cell Dev Biol Cell and Developmental Biology The tumor suppressor p53 is critical for the maintenance of genome stability and protection against tumor malignant transformation, and its homeostasis is usually regulated by ubiquitination. MDM2 is a major E3 ligase of p53 ubiquitination, and its activity is enhanced by TRIM28. TRIM28 also independently ubiquitinates p53 as an E3 ligase activated by MAGE-C2. Moreover, MAGE-C2 is highly expressed in various cancers, but the detailed mechanisms of MAGE-C2 involved in MDM2/TRIM28-mediated p53 ubiquitination remain unknown. Here, we found that MAGE-C2 directly interacts with MDM2 through its conserved MHD domain to inhibit the activity of MDM2 on p53 ubiquitination. Furthermore, TRIM28 acts as an MAGE-C2 binding partner and directly competes with MAGE-C2 for MDM2 interaction, thus releasing the inhibitory role of MAGE-C2 and promoting p53 ubiquitination. MAGE-C2 suppresses cell proliferation in TRIM28-deficient cells, but the overexpression of TRIM28 antagonizes the inhibitory role of MAGE-C2 and accumulates p53 ubiquitination to promote cell proliferation. This study clarified the molecular link of MAGE-C2 in two major E3 systems MDM2 and TRIM28 on p53 ubiquitination. Our results revealed the molecular function of how MAGE-C2 and TRIM28 contribute to p53 ubiquitination and cell proliferation, in which MAGE-C2 acts as a potential inhibitor of MDM2 and TRIM28 is a vital regulator for MAGE-C2 function in p53 protein level and cell proliferation. This work would be helpful to understand the regulation mechanism of tumor suppressor p53. Frontiers Media S.A. 2022-07-19 /pmc/articles/PMC9344466/ /pubmed/35927984 http://dx.doi.org/10.3389/fcell.2022.922675 Text en Copyright © 2022 Liu, Cao, Hu, Ye, Tian and He. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Cell and Developmental Biology Liu, Yunshan Cao, Beibei Hu, Liqiao Ye, Jingjing Tian, Wei He, Xiaojing The Dual Roles of MAGE-C2 in p53 Ubiquitination and Cell Proliferation Through E3 Ligases MDM2 and TRIM28 |
title | The Dual Roles of MAGE-C2 in p53 Ubiquitination and Cell Proliferation Through E3 Ligases MDM2 and TRIM28 |
title_full | The Dual Roles of MAGE-C2 in p53 Ubiquitination and Cell Proliferation Through E3 Ligases MDM2 and TRIM28 |
title_fullStr | The Dual Roles of MAGE-C2 in p53 Ubiquitination and Cell Proliferation Through E3 Ligases MDM2 and TRIM28 |
title_full_unstemmed | The Dual Roles of MAGE-C2 in p53 Ubiquitination and Cell Proliferation Through E3 Ligases MDM2 and TRIM28 |
title_short | The Dual Roles of MAGE-C2 in p53 Ubiquitination and Cell Proliferation Through E3 Ligases MDM2 and TRIM28 |
title_sort | dual roles of mage-c2 in p53 ubiquitination and cell proliferation through e3 ligases mdm2 and trim28 |
topic | Cell and Developmental Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9344466/ https://www.ncbi.nlm.nih.gov/pubmed/35927984 http://dx.doi.org/10.3389/fcell.2022.922675 |
work_keys_str_mv | AT liuyunshan thedualrolesofmagec2inp53ubiquitinationandcellproliferationthroughe3ligasesmdm2andtrim28 AT caobeibei thedualrolesofmagec2inp53ubiquitinationandcellproliferationthroughe3ligasesmdm2andtrim28 AT huliqiao thedualrolesofmagec2inp53ubiquitinationandcellproliferationthroughe3ligasesmdm2andtrim28 AT yejingjing thedualrolesofmagec2inp53ubiquitinationandcellproliferationthroughe3ligasesmdm2andtrim28 AT tianwei thedualrolesofmagec2inp53ubiquitinationandcellproliferationthroughe3ligasesmdm2andtrim28 AT hexiaojing thedualrolesofmagec2inp53ubiquitinationandcellproliferationthroughe3ligasesmdm2andtrim28 AT liuyunshan dualrolesofmagec2inp53ubiquitinationandcellproliferationthroughe3ligasesmdm2andtrim28 AT caobeibei dualrolesofmagec2inp53ubiquitinationandcellproliferationthroughe3ligasesmdm2andtrim28 AT huliqiao dualrolesofmagec2inp53ubiquitinationandcellproliferationthroughe3ligasesmdm2andtrim28 AT yejingjing dualrolesofmagec2inp53ubiquitinationandcellproliferationthroughe3ligasesmdm2andtrim28 AT tianwei dualrolesofmagec2inp53ubiquitinationandcellproliferationthroughe3ligasesmdm2andtrim28 AT hexiaojing dualrolesofmagec2inp53ubiquitinationandcellproliferationthroughe3ligasesmdm2andtrim28 |