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TRAF4 Inhibits the Apoptosis and Promotes the Proliferation of Breast Cancer Cells by Inhibiting the Ubiquitination of Spindle Assembly-Associated Protein Eg5

Tumor necrosis factor receptor associated factor 4 (TRAF4) is a RING domain E3 ubiquitin ligase that mediates the ubiquitination of various proteins and plays an important role in driving tumor progression. By studying the relationship between TRAF4 and Eg5, a member of the kinesin family that plays...

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Autores principales: Hao, Miaomiao, Zhang, Jie, Sun, Mingfang, Diao, Kexin, Wang, Jian, Li, Shiping, Cao, Qixue, Dai, Shundong, Mi, Xiaoyi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9174544/
https://www.ncbi.nlm.nih.gov/pubmed/35692762
http://dx.doi.org/10.3389/fonc.2022.855139
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author Hao, Miaomiao
Zhang, Jie
Sun, Mingfang
Diao, Kexin
Wang, Jian
Li, Shiping
Cao, Qixue
Dai, Shundong
Mi, Xiaoyi
author_facet Hao, Miaomiao
Zhang, Jie
Sun, Mingfang
Diao, Kexin
Wang, Jian
Li, Shiping
Cao, Qixue
Dai, Shundong
Mi, Xiaoyi
author_sort Hao, Miaomiao
collection PubMed
description Tumor necrosis factor receptor associated factor 4 (TRAF4) is a RING domain E3 ubiquitin ligase that mediates the ubiquitination of various proteins and plays an important role in driving tumor progression. By studying the relationship between TRAF4 and Eg5, a member of the kinesin family that plays a critical role in spindle assembly, we demonstrated that TRAF4 regulated Eg5 ubiquitination and contributed to Eg5-mediated breast cancer proliferation and inhibited breast cancer apoptosis. TRAF4 and Eg5 were both highly expressed in breast cancer and their protein level was positively correlated. Relying on its Zinc fingers domain, TRAF4 interacted with Eg5 in the cytoplasm of breast cancer cells. TRAF4 was a mitosis-related protein, and by up-regulating the protein level of Eg5 TRAF4 participated in spindle assembly. Loss of TRAF4 resulted in monopolar spindles formation, but loss of function could be rescued by Eg5. Relying on its RING domain, TRAF4 up-regulated Eg5 protein levels by inhibition of Eg5 ubiquitination, thus stabilizing Eg5 protein level during mitosis. Furthermore, we found that Smurf2, a TRAF4-targeted ubiquitination substrate, mediated the regulation of Eg5 ubiquitination by TRAF4. TRAF4 inhibited the interaction between Smurf2 and Eg5, and down-regulated the protein level of Smurf2 by promoting its ubiquitination, thereby inhibited the Smurf2-catalyzed ubiquitination of Eg5 and up-regulated Eg5 protein levels. We also demonstrate that TRAF4 plays an important role in promoting cell proliferation and in inhibiting cell apoptosis induced by Eg5. In summary, our study suggests a new direction for investigating the role of TRAF4 in driving breast cancer progression.
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spelling pubmed-91745442022-06-09 TRAF4 Inhibits the Apoptosis and Promotes the Proliferation of Breast Cancer Cells by Inhibiting the Ubiquitination of Spindle Assembly-Associated Protein Eg5 Hao, Miaomiao Zhang, Jie Sun, Mingfang Diao, Kexin Wang, Jian Li, Shiping Cao, Qixue Dai, Shundong Mi, Xiaoyi Front Oncol Oncology Tumor necrosis factor receptor associated factor 4 (TRAF4) is a RING domain E3 ubiquitin ligase that mediates the ubiquitination of various proteins and plays an important role in driving tumor progression. By studying the relationship between TRAF4 and Eg5, a member of the kinesin family that plays a critical role in spindle assembly, we demonstrated that TRAF4 regulated Eg5 ubiquitination and contributed to Eg5-mediated breast cancer proliferation and inhibited breast cancer apoptosis. TRAF4 and Eg5 were both highly expressed in breast cancer and their protein level was positively correlated. Relying on its Zinc fingers domain, TRAF4 interacted with Eg5 in the cytoplasm of breast cancer cells. TRAF4 was a mitosis-related protein, and by up-regulating the protein level of Eg5 TRAF4 participated in spindle assembly. Loss of TRAF4 resulted in monopolar spindles formation, but loss of function could be rescued by Eg5. Relying on its RING domain, TRAF4 up-regulated Eg5 protein levels by inhibition of Eg5 ubiquitination, thus stabilizing Eg5 protein level during mitosis. Furthermore, we found that Smurf2, a TRAF4-targeted ubiquitination substrate, mediated the regulation of Eg5 ubiquitination by TRAF4. TRAF4 inhibited the interaction between Smurf2 and Eg5, and down-regulated the protein level of Smurf2 by promoting its ubiquitination, thereby inhibited the Smurf2-catalyzed ubiquitination of Eg5 and up-regulated Eg5 protein levels. We also demonstrate that TRAF4 plays an important role in promoting cell proliferation and in inhibiting cell apoptosis induced by Eg5. In summary, our study suggests a new direction for investigating the role of TRAF4 in driving breast cancer progression. Frontiers Media S.A. 2022-05-25 /pmc/articles/PMC9174544/ /pubmed/35692762 http://dx.doi.org/10.3389/fonc.2022.855139 Text en Copyright © 2022 Hao, Zhang, Sun, Diao, Wang, Li, Cao, Dai and Mi 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 Oncology
Hao, Miaomiao
Zhang, Jie
Sun, Mingfang
Diao, Kexin
Wang, Jian
Li, Shiping
Cao, Qixue
Dai, Shundong
Mi, Xiaoyi
TRAF4 Inhibits the Apoptosis and Promotes the Proliferation of Breast Cancer Cells by Inhibiting the Ubiquitination of Spindle Assembly-Associated Protein Eg5
title TRAF4 Inhibits the Apoptosis and Promotes the Proliferation of Breast Cancer Cells by Inhibiting the Ubiquitination of Spindle Assembly-Associated Protein Eg5
title_full TRAF4 Inhibits the Apoptosis and Promotes the Proliferation of Breast Cancer Cells by Inhibiting the Ubiquitination of Spindle Assembly-Associated Protein Eg5
title_fullStr TRAF4 Inhibits the Apoptosis and Promotes the Proliferation of Breast Cancer Cells by Inhibiting the Ubiquitination of Spindle Assembly-Associated Protein Eg5
title_full_unstemmed TRAF4 Inhibits the Apoptosis and Promotes the Proliferation of Breast Cancer Cells by Inhibiting the Ubiquitination of Spindle Assembly-Associated Protein Eg5
title_short TRAF4 Inhibits the Apoptosis and Promotes the Proliferation of Breast Cancer Cells by Inhibiting the Ubiquitination of Spindle Assembly-Associated Protein Eg5
title_sort traf4 inhibits the apoptosis and promotes the proliferation of breast cancer cells by inhibiting the ubiquitination of spindle assembly-associated protein eg5
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9174544/
https://www.ncbi.nlm.nih.gov/pubmed/35692762
http://dx.doi.org/10.3389/fonc.2022.855139
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