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Lack of the AHR leads to impaired activation of Akt/PKB and enhanced sensitivity to UV‐induced apoptosis in murine hepatoma cells
Author(s) -
Wu Ran,
Swanson Hollie
Publication year - 2006
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.20.4.a259-c
Subject(s) - protein kinase b , apoptosis , cancer research , microbiology and biotechnology , chemistry , sensitivity (control systems) , biology , biochemistry , electronic engineering , engineering
The aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor that is best known for its role in mediating the toxicity of many environmental contaminants such as 2,3,7,8 tetrachlorodibenzo‐p‐dioxin. However, the endogenous role of AHR especially with respect to the apoptotic process is largely unknown and contradictive. In this report, we used mouse hepatoma cells (Hepa1c1c7) and its AHR‐deficient derivative (LA1) to examine the effect of differing AHR levels on apoptosis susceptibility. In this study, we focused on the intrinsic pathway of apoptosis and thus used UV irradiation, hydrogen peroxide and serum starvation as the apoptotic stimuli. Analyses of a number of different endpoints of apoptosis revealed that the LA1 cells were more responsive to these apoptotic stresses than Hepa1c1c7 cells indicating that the AHR plays a protective role to apoptosis initiated by the intrinsic pathway. A direct role of the AHR in mediating this cytoprotective effect was confirmed using both pharmacological (i.e., use of the AHR antagonist 3′‐methoxy‐4′‐nitroflavone) and molecular (i.e., restoration of AHR expression levels in the LA1 cells) approaches. Mechanistic examination of this phenomenon revealed that lack of the AHR leads to an impaired prosurvival pathway mediated by Akt/PKB phosphorylation and the EGFR. These results demonstrate that the AHR is an important determinant of apoptosis susceptibility that is mediated in part, by its ability to inhibit survival mechanisms that include phosphorylation of Akt/PKB.