Fbxo45-mediated degradation of the tumor-suppressor Par-4 regulates cancer cell survival

X. Chen; A. A. Sahasrabuddhe; P. Szankasi; F. Chung; V. Basrur; V. M. Rangnekar; M. Pagano; M. S. Lim; K. S.J. Elenitoba-Johnson

doi:10.1038/cdd.2014.92

Fbxo45-mediated degradation of the tumor-suppressor Par-4 regulates cancer cell survival

X. Chen, A. A. Sahasrabuddhe, P. Szankasi, F. Chung, V. Basrur, V. M. Rangnekar, M. Pagano, M. S. Lim, K. S.J. Elenitoba-Johnson

Research output: Contribution to journal › Article › peer-review

45 Scopus citations

Abstract

Prostate apoptosis response protein 4 (Par-4) also known as PRKC apoptosis WT1 regulator is a tumor suppressor that selectively induces apoptosis in cancer cells. However, its post-translational regulation by ubiquitin-mediated proteolysis and the cellular machinery that is responsible for its proteasomal degradation are unknown. Using immunopurification and an unbiased mass spectrometry-based approach, we show that Par-4 interacts with the SPRY-domain containing E3 ubiquitin ligase Fbxo45 through a short consensus sequence motif. Fbxo45 interacts with Par-4 in the cytoplasm and mediates its ubiquitylation and proteasomal degradation. Fbxo45 silencing results in stabilization of Par-4 with increased apoptosis. Importantly, a Par-4 mutant that is unable to bind Fbxo45 is stabilized and further enhances staurosporine-induced apoptosis. Co-expression of Fbxo45 with Par-4 protects cancer cells against Par-4-induced apoptosis. Our studies reveal that Fbxo45 is the substrate-receptor subunit of a functional E3 ligase for Par-4 that has a critical role in cancer cell survival.

Original language	English
Pages (from-to)	1535-1545
Number of pages	11
Journal	Cell Death and Differentiation
Volume	21
Issue number	10
DOIs	https://doi.org/10.1038/cdd.2014.92
State	Published - Oct 1 2014

Bibliographical note

Funding Information:
Acknowledgements. We thank Dr. Joon-Young Ahn for his assistance with the characterization of the anti-Fbxo45 polyclonal antibody. This work was funded by NIH grants R01 DE119249 and R01 CA136905 to KSJE-J and R01 CA140806 to MSL

Publisher Copyright:
© 2014 Macmillan Publishers Limited All rights reserved.

ASJC Scopus subject areas

Molecular Biology
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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title = "Fbxo45-mediated degradation of the tumor-suppressor Par-4 regulates cancer cell survival",

abstract = "Prostate apoptosis response protein 4 (Par-4) also known as PRKC apoptosis WT1 regulator is a tumor suppressor that selectively induces apoptosis in cancer cells. However, its post-translational regulation by ubiquitin-mediated proteolysis and the cellular machinery that is responsible for its proteasomal degradation are unknown. Using immunopurification and an unbiased mass spectrometry-based approach, we show that Par-4 interacts with the SPRY-domain containing E3 ubiquitin ligase Fbxo45 through a short consensus sequence motif. Fbxo45 interacts with Par-4 in the cytoplasm and mediates its ubiquitylation and proteasomal degradation. Fbxo45 silencing results in stabilization of Par-4 with increased apoptosis. Importantly, a Par-4 mutant that is unable to bind Fbxo45 is stabilized and further enhances staurosporine-induced apoptosis. Co-expression of Fbxo45 with Par-4 protects cancer cells against Par-4-induced apoptosis. Our studies reveal that Fbxo45 is the substrate-receptor subunit of a functional E3 ligase for Par-4 that has a critical role in cancer cell survival.",

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note = "Funding Information: Acknowledgements. We thank Dr. Joon-Young Ahn for his assistance with the characterization of the anti-Fbxo45 polyclonal antibody. This work was funded by NIH grants R01 DE119249 and R01 CA136905 to KSJE-J and R01 CA140806 to MSL Publisher Copyright: {\textcopyright} 2014 Macmillan Publishers Limited All rights reserved.",

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AU - Chung, F.

AU - Basrur, V.

AU - Rangnekar, V. M.

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AU - Lim, M. S.

AU - Elenitoba-Johnson, K. S.J.

N1 - Funding Information: Acknowledgements. We thank Dr. Joon-Young Ahn for his assistance with the characterization of the anti-Fbxo45 polyclonal antibody. This work was funded by NIH grants R01 DE119249 and R01 CA136905 to KSJE-J and R01 CA140806 to MSL Publisher Copyright: © 2014 Macmillan Publishers Limited All rights reserved.

PY - 2014/10/1

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N2 - Prostate apoptosis response protein 4 (Par-4) also known as PRKC apoptosis WT1 regulator is a tumor suppressor that selectively induces apoptosis in cancer cells. However, its post-translational regulation by ubiquitin-mediated proteolysis and the cellular machinery that is responsible for its proteasomal degradation are unknown. Using immunopurification and an unbiased mass spectrometry-based approach, we show that Par-4 interacts with the SPRY-domain containing E3 ubiquitin ligase Fbxo45 through a short consensus sequence motif. Fbxo45 interacts with Par-4 in the cytoplasm and mediates its ubiquitylation and proteasomal degradation. Fbxo45 silencing results in stabilization of Par-4 with increased apoptosis. Importantly, a Par-4 mutant that is unable to bind Fbxo45 is stabilized and further enhances staurosporine-induced apoptosis. Co-expression of Fbxo45 with Par-4 protects cancer cells against Par-4-induced apoptosis. Our studies reveal that Fbxo45 is the substrate-receptor subunit of a functional E3 ligase for Par-4 that has a critical role in cancer cell survival.

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Fbxo45-mediated degradation of the tumor-suppressor Par-4 regulates cancer cell survival

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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