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2017 ; 33
(3
): 211-218
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CYP1B1 Activates Wnt/?-Catenin Signaling through Suppression of Herc5-Mediated
ISGylation for Protein Degradation on ?-Catenin in HeLa Cells
#MMPMID28744352
Park YS
; Kwon YJ
; Chun YJ
Toxicol Res
2017[Jul]; 33
(3
): 211-218
PMID28744352
show ga
Cytochrome P450 1B1 (CYP1B1) acts as a hydroxylase for estrogen and activates
potential carcinogens. Moreover, its expression in tumor tissues is much higher
than that in normal tissues. Despite this association between CYP1B1 and cancer,
the detailed molecular mechanism of CYP1B1 on cancer progression in HeLa cells
remains unknown. Previous reports indicated that the mRNA expression level of
Herc5, an E3 ligase for ISGylation, is promoted by CYP1B1 suppression using
specific small interfering RNA, and that ISGylation may be involved in
ubiquitination related to ?-catenin degradation. With this background, we
investigated the relationships among CYP1B1, Herc5, and ?-catenin. RT-PCR and
western blot analyses showed that CYP1B1 overexpression induced and CYP1B1
inhibition reduced, respectively, the expression of Wnt/?-catenin signaling
target genes including ?-catenin and cyclin D1. Moreover, HeLa cells were treated
with the CYP1B1 inducer 7,12-dimethylbenz[?]anthracene (DMBA) or the CYP1B1
specific inhibitor, tetramethoxystilbene (TMS) and consequently DMBA increased
and TMS decreased ?-catenin and cyclin D1 expression, respectively. To determine
the correlation between CYP1B1 expression and ISGylation, the expression of
ISG15, a ubiquitin-like protein, was detected following CYP1B1 regulation, which
revealed that CYP1B1 may inhibit ISGylation through suppression of ISG15
expression. In addition, the mRNA and protein expression levels of Herc5 were
strongly suppressed by CYP1B1. Finally, an immunoprecipitation assay revealed a
direct physical interaction between Herc5 and ?-catenin in HeLa cells. In
conclusion, these data suggest that CYP1B1 may activate Wnt/?-catenin signaling
through stabilization of ?-catenin protein from Herc5-mediated ISGylation for
proteosomal degradation.