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The Cyclophilin CyP40 is necessary for the Ligand‐Dependent Aryl Hydrocarbon Receptor Signaling in Human Breast Cancer Cells
Author(s) -
Luu Tony C,
Bhattacharya Pompeya,
Chan William K
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.921.3
Subject(s) - aryl hydrocarbon receptor nuclear translocator , aryl hydrocarbon receptor , gene knockdown , transcription factor , signal transduction , biology , microbiology and biotechnology , chemistry , cancer research , biochemistry , gene
The aryl hydrocarbon receptor (AhR) is a ligand‐activated transcription factor that heterodimerizes with AhR nuclear translocator (Arnt) to regulate expression of genes such as cyp1a1 . Our previous data from in vitro protein‐DNA interaction studies revealed that a cyclophilin called CyP40 restores the ligand‐dependent AhR/Arnt/DRE complex formation. Although it has been known that CyP40 is involved in Hsp90‐dependent signaling pathways, the role of CyP40 in the AhR signaling has not been established. In order to investigate the role of CyP40 in AhR signaling, we performed CyP40 knockdown studies in MCF‐7 cells to address whether CyP40 is essential for cyp1a1 induction by an AhR ligand. Real‐time PCR data showed that when CyP40 expression in MCF‐7 cells was reduced to 30–40% of its endogenous level by two independent siRNAs, approximately 50% decrease in 3‐methylchloranthrene‐induced cyp1a1 message was observed ( p <0.05). In addition, we mapped the essential CyP40 domain for restoring the AhR/Arnt/DRE complex formation by generating three CyP40 deletion constructs as 6‐His fusions. We found that the amino acid residues 186–215 were necessary for CyP40 to restore the AhR/Arnt/DRE complex formation in a gel shift assay. Data from various protein interaction studies suggest that CyP40 may interact with AhR to elicit the CyP40 effect on the AhR signaling. This work is supported by a grant from the National Institute of Health (R01ES014050).