TY - JOUR
T1 - Fbxo45-mediated degradation of the tumor-suppressor Par-4 regulates cancer cell survival
AU - Chen, X.
AU - Sahasrabuddhe, A. A.
AU - Szankasi, P.
AU - Chung, F.
AU - Basrur, V.
AU - Rangnekar, V. M.
AU - Pagano, M.
AU - Lim, M. S.
AU - Elenitoba-Johnson, K. S.J.
N1 - Publisher Copyright:
© 2014 Macmillan Publishers Limited All rights reserved.
PY - 2014/10/1
Y1 - 2014/10/1
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.
AB - 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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U2 - 10.1038/cdd.2014.92
DO - 10.1038/cdd.2014.92
M3 - Article
C2 - 24992930
AN - SCOPUS:84964241086
SN - 1350-9047
VL - 21
SP - 1535
EP - 1545
JO - Cell Death and Differentiation
JF - Cell Death and Differentiation
IS - 10
ER -