Aryl Hydrocarbon Receptor Regulates Cell Cycle Progression in Human Breast Cancer Cells via a Functional Interaction with Cyclin-Dependent Kinase 4

Abstract

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 D-cyclin-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.The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor and a member of the basic helix-loophelix, period/aryl hydrocarbon receptor nuclear translocator (ARNT)/single-minded (PAS) superfamily. In the canonical model for AHR signaling, the unliganded form of the receptor exists in the cytoplasm in a stable complex with HSP90,

Edible flowers — antioxidant activity and impact on cell viability

“…For example, resveratrol [43], detected in a huge amount in V. arvensis flowers and in smaller amounts in R. acetosa, C. intybus, B. perennis, T. officinale and T. pratensis flowers has the ability to bind to both estrogen receptors and act as a mixed agonist/ antagonist. Consequently, resveratrol can have a potent effect, even in low-doses, through the aryl hydrocarbon receptor [44] that plays an important role in cancer cells [45]. Resveratrol not only influences estrogen receptors, but down-regulates the nuclear factor-KB [46], another important therapeutic target.…”

The Aryl Hydrocarbon Receptor Contributes to the Proliferation of Human Medulloblastoma Cells

“…AhR was shown to regulate cell cycle progression in human breast cancer cells via a functional interaction with cyclin-dependent kinase 4, but treatment with TCDD disrupted this complex, resulting in cell cycle arrest (Barhoover et al, 2010). However, there have been conflicting reports regarding the function of AhR as a cell cycle regulator, which may be due to differential responses in various cell types.…”

p-Anilinoaniline Enhancement of Dioxin-Induced CYP1A1 Transcription and Aryl Hydrocarbon Receptor Occupancy of CYP1A1 Promoter: Role of the Cell Cycle

“…For example, contact inhibited, quiescent rat liver epithelial WB-F344 cultures reenter the cell cycle and proliferate after exposure to TCDD and several polychlorinated biphenyl and polycyclic aromatic hydrocarbon AhR agonists (Chramostová et al, 2004;Vondrácek et al, 2005). In contrast, TCDD induces a profound G 1 or S phase arrest in a variety of cultured cell types (reviewed by Marlowe and Puga, 2005;Puga et al, 2009;Barhoover et al, 2010). In many cases, this arrest has been shown to be AhR-dependent (Marlowe and Puga, 2005).…”