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United States: American Society for Pharmacology and Experimental Therapeutics
Erscheinungsjahr
2010
Link zum Volltext
Quelle
Free E-Journal (出版社公開部分のみ）
Beschreibungen/Notizen
The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor with constitutive activities and those induced
by xenobiotic ligands, such as 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD). One unexplained cellular role for the AHR is its ability to promote cell cycle progression in the absence
of exogenous ligands, whereas treatment with exogenous ligands induces cell cycle arrest. Within the cell cycle, progression
from G 1 to S phase is controlled by sequential phosphorylation of the retinoblastoma protein (RB1) by cyclin Dâcyclin-dependent kinase
(CDK) 4/6 complexes. In this study, the functional interactions between the AHR, CDK4, and cyclin D1 (CCND1) were investigated
as a potential mechanism for the cell cycle regulation by the AHR. Time course cell cycle and molecular experiments were performed
in human breast cancer cells. The results demonstrated that the AHR and CDK4 interact within the cell cycle, and the interaction
was disrupted upon TCDD treatment. The disruption was temporally correlated with G 1 cell cycle arrest and decreased phosphorylation of RB1. Biochemical reconstitution assays using in vitro-translated protein
recapitulated the AHR and CDK4 interaction and showed that CCND1 was also part of the complex. In vitro assays for CDK4 kinase
activity demonstrated that RB1 phosphorylation by the AHR/CDK4/CCND1 complex was reduced in the presence of TCDD. The results
suggest that the AHR interacts in a complex with CDK4 and CCND1 in the absence of exogenous ligands to facilitate cell cycle
progression. This interaction is disrupted by exogenous ligands, such as TCDD, to induce G 1 cell cycle arrest.