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Analysis of Cell Cycle Position in Mammalian Cells
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Aromatic hydrocarbon receptor interaction with the retinoblastoma protein potentiates repression of E2F-dependent

A Puga1, S J Barnes, T P Dalton

  • 1Center for Environmental Genetics, Department of Environmental Health, University of Cincinnati Medical Center, Cincinnati, Ohio 45267-0056, USA. Alvaro.Puga@UC.EDU

The Journal of Biological Chemistry
|January 25, 2000
PubMed

Insights

The aromatic hydrocarbon receptor (AHR) interacts with the retinoblastoma protein (RB) to regulate cell cycle progression. This interaction, triggered by environmental toxicants like TCDD, signals cell cycle arrest.

Area of Science:

  • Toxicology
  • Molecular Biology
  • Cell Cycle Regulation

Background:

  • Polyhalogenated aromatic hydrocarbons, such as 2,3,7,8-tetrachloro-p-dioxin (TCDD), induce toxic, teratogenic, and carcinogenic effects.
  • TCDD impacts cell cycle progression in various cell types, including apoptosis, proliferation, and differentiation.
  • The dioxin aromatic hydrocarbon receptor (AHR) contains an LXCXE domain, suggesting a role in protein-protein interactions affecting cell cycle regulation.

Purpose of the Study:

  • To investigate the potential interaction between the AHR and the retinoblastoma protein (RB) in mediating TCDD's effects on cell cycle regulation.
  • To elucidate the mechanism by which AHR influences cell cycle progression in response to environmental toxicants.

Main Methods:

  • Yeast two-hybrid system to assess AHR-RB binding.
  • In vitro pull-down assays using truncated AHR peptides.
  • Coimmunoprecipitation from human breast carcinoma MCF-7 cells.
  • Ectopic expression of AHR and RB in human osteosarcoma SAOS-2 cells.

Main Results:

  • AHR and RB were shown to bind to each other using the yeast two-hybrid system.
  • AHR forms independent complexes with hypophosphorylated RB through at least two separate domains.
  • AHR associates with RB in vivo in MCF-7 cells upon receptor transformation and nuclear translocation.
  • AHR and RB synergistically repress E2F-dependent transcription and induce cell cycle arrest in SAOS-2 cells.
  • AHR partially inhibited T-antigen-mediated reversal of RB-dependent transcriptional repression.

Conclusions:

  • The AHR directly interacts with RB, influencing cell cycle control.
  • This AHR-RB interaction plays a role in mediating the cellular response to environmental toxicants.
  • The AHR may function as an environmental sensor, signaling cell cycle arrest upon exposure to certain toxicants.

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