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Modulation of multidrug resistance in cancer cells by the E3 ubiquitin ligase seven‐in‐absentia homologue 1
Author(s) -
Liu M,
Aneja R,
Wang H,
Sun L,
Dong X,
Huo L,
Joshi HC,
Zhou J
Publication year - 2008
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.2312
Subject(s) - ubiquitin ligase , ubiquitin , biology , microbiology and biotechnology , multiple drug resistance , c jun , activator (genetics) , p glycoprotein , kinase , dna ligase , phosphorylation , cancer research , transcription factor , drug resistance , receptor , biochemistry , gene , genetics
Seven‐in‐absentia homologue 1 (Siah1) is an E3 ubiquitin ligase that regulates the ubiquitination and proteasome‐dependent degradation of a number of proteins. Here we report that Siah1 modulates multidrug resistance 1 (MDR1)/P‐glycoprotein‐mediated drug resistance in the cancer cell lines examined. Siah1, but not its ligase‐dead mutant, down‐regulates MDR1/P‐glycoprotein and sensitizes the multidrug‐resistant cells to chemotherapeutic agents. Mechanistically, Siah1 does not promote P‐glycoprotein degradation but decreases its expression transcriptionally by promoting c‐Jun transcription factor binding to the activator protein 1 (AP1) site in the MDR1 promoter. Moreover, Siah1 triggers c‐Jun NH 2 ‐terminal kinase (JNK) activation, leading to enhanced phosphorylation of c‐Jun, and the JNK/c‐Jun signalling axis is critical for Siah1 to down‐regulate MDR1/P‐glycoprotein expression. These findings demonstrate a previously unidentified role for Siah1 in regulating MDR1/P‐glycoprotein expression through the JNK/c‐Jun pathway. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.