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J Pathol. 2008 Mar;214(4):508-14. doi: 10.1002/path.2312.

Modulation of multidrug resistance in cancer cells by the E3 ubiquitin ligase seven-in-absentia homologue 1.

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  • 1Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin 300071, People's Republic of China.

Abstract

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 NH2-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.

PMID:
18213731
[PubMed - indexed for MEDLINE]
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