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Parkin regulates IGF2BP3 through ubiquitination in the tumourigenesis of cervical cancer

BACKGROUND: Insulin‐like growth Factor 2 mRNA‐binding protein 3 (IGF2BP3) is a highly conserved RNA‐binding protein and plays a critical role in regulating posttranscriptional modifications. METHODS: Immunoprecipitation was used to examine the interaction of Parkin and IGF2BP3. Mass spectrometry was...

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Autores principales: Sun, Xin, Ye, Guiqin, Li, Jiuzhou, Shou, Huafeng, Bai, Gongxun, Zhang, Jianbin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10599278/
https://www.ncbi.nlm.nih.gov/pubmed/37877353
http://dx.doi.org/10.1002/ctm2.1457
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author Sun, Xin
Ye, Guiqin
Li, Jiuzhou
Shou, Huafeng
Bai, Gongxun
Zhang, Jianbin
author_facet Sun, Xin
Ye, Guiqin
Li, Jiuzhou
Shou, Huafeng
Bai, Gongxun
Zhang, Jianbin
author_sort Sun, Xin
collection PubMed
description BACKGROUND: Insulin‐like growth Factor 2 mRNA‐binding protein 3 (IGF2BP3) is a highly conserved RNA‐binding protein and plays a critical role in regulating posttranscriptional modifications. METHODS: Immunoprecipitation was used to examine the interaction of Parkin and IGF2BP3. Mass spectrometry was performed to identify the ubiquitination sites of IGF2BP3. RNA‐immunoprecipitation was conducted to examine the target genes of IGF2BP3. Xenograft mouse model was constructed to determine the tumorigenesis of IGF2BP3. RESULTS: IGF2BP3 expression is negatively correlated with Parkin expression in human cervical cancer cells and tissues. Parkin directly interacts with IGF2BP3, and overexpression of Parkin causes the proteasomal degradation of IGF2BP3, while knockdown of PARK2 increases the protein levels of IGF2BP3. Mechanistically, in vivo and in vitro ubiquitination assays demonstrated that Parkin is able to ubiquitinate IGF2BP3. Moreover, the ubiquitination site of IGF2BP3 was identified at K213 in the first KH domain of IGF2BP3. IGF2BP3 mutation results in the loss of its oncogenic function as an m6A reader, resulting in the inactivation of the phosphoinositide 3‐kinase (PI3K) and mitogen‐activated protein kinase (MAPK) signalling pathways. In addition, IGF2BP3 mutation results in the attenuation of Parkin‐mediated mitophagy, indicating its inverse role in regulating Parkin. Consequently, the tumourigenesis of cervical cancer is also inhibited by IGF2BP3 mutation. CONCLUSION: IGF2BP3 is ubiquitinated and regulated by the E3 ubiquitin ligase Parkin in human cervical cancer and ubiquitination modification plays an important role in modulating IGF2BP3 function. Thus, understanding the role of IGF2BP3 in tumourigenesis could provide new insights into cervical cancer therapy.
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spelling pubmed-105992782023-10-26 Parkin regulates IGF2BP3 through ubiquitination in the tumourigenesis of cervical cancer Sun, Xin Ye, Guiqin Li, Jiuzhou Shou, Huafeng Bai, Gongxun Zhang, Jianbin Clin Transl Med Research Articles BACKGROUND: Insulin‐like growth Factor 2 mRNA‐binding protein 3 (IGF2BP3) is a highly conserved RNA‐binding protein and plays a critical role in regulating posttranscriptional modifications. METHODS: Immunoprecipitation was used to examine the interaction of Parkin and IGF2BP3. Mass spectrometry was performed to identify the ubiquitination sites of IGF2BP3. RNA‐immunoprecipitation was conducted to examine the target genes of IGF2BP3. Xenograft mouse model was constructed to determine the tumorigenesis of IGF2BP3. RESULTS: IGF2BP3 expression is negatively correlated with Parkin expression in human cervical cancer cells and tissues. Parkin directly interacts with IGF2BP3, and overexpression of Parkin causes the proteasomal degradation of IGF2BP3, while knockdown of PARK2 increases the protein levels of IGF2BP3. Mechanistically, in vivo and in vitro ubiquitination assays demonstrated that Parkin is able to ubiquitinate IGF2BP3. Moreover, the ubiquitination site of IGF2BP3 was identified at K213 in the first KH domain of IGF2BP3. IGF2BP3 mutation results in the loss of its oncogenic function as an m6A reader, resulting in the inactivation of the phosphoinositide 3‐kinase (PI3K) and mitogen‐activated protein kinase (MAPK) signalling pathways. In addition, IGF2BP3 mutation results in the attenuation of Parkin‐mediated mitophagy, indicating its inverse role in regulating Parkin. Consequently, the tumourigenesis of cervical cancer is also inhibited by IGF2BP3 mutation. CONCLUSION: IGF2BP3 is ubiquitinated and regulated by the E3 ubiquitin ligase Parkin in human cervical cancer and ubiquitination modification plays an important role in modulating IGF2BP3 function. Thus, understanding the role of IGF2BP3 in tumourigenesis could provide new insights into cervical cancer therapy. John Wiley and Sons Inc. 2023-10-25 /pmc/articles/PMC10599278/ /pubmed/37877353 http://dx.doi.org/10.1002/ctm2.1457 Text en © 2023 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Sun, Xin
Ye, Guiqin
Li, Jiuzhou
Shou, Huafeng
Bai, Gongxun
Zhang, Jianbin
Parkin regulates IGF2BP3 through ubiquitination in the tumourigenesis of cervical cancer
title Parkin regulates IGF2BP3 through ubiquitination in the tumourigenesis of cervical cancer
title_full Parkin regulates IGF2BP3 through ubiquitination in the tumourigenesis of cervical cancer
title_fullStr Parkin regulates IGF2BP3 through ubiquitination in the tumourigenesis of cervical cancer
title_full_unstemmed Parkin regulates IGF2BP3 through ubiquitination in the tumourigenesis of cervical cancer
title_short Parkin regulates IGF2BP3 through ubiquitination in the tumourigenesis of cervical cancer
title_sort parkin regulates igf2bp3 through ubiquitination in the tumourigenesis of cervical cancer
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10599278/
https://www.ncbi.nlm.nih.gov/pubmed/37877353
http://dx.doi.org/10.1002/ctm2.1457
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