Maximal Aryl Hydrocarbon Receptor Activity Depends on an Interaction with the Retinoblastoma Protein
Abstract
The aryl hydrocarbon receptor (AhR) belongs to the basic helix-loop-helix/periodicity/AhR nuclear translocator/simple-minded (Per-Arnt-Sim) family of transcription factors that regulate critical functions during development and tissue homeostasis. Within this family, the AhR is the only member conditionally activated in response to ligand binding, typified by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). We recently demonstrated that the AhR interacts with the retinoblastoma protein (pRb). This report presents evidence that a LXCXE motif in the AhR protein confers pRb binding, which is necessary for maximal TCDD induced G1 arrest in rat 5L hepatoma cells. The data support a mechanism whereby pRb seems to regulate G1 cell cycle progression distinct from the direct repression of E2F-mediated transcription. Furthermore, the results indicate that the AhR-pRb interaction regulates TCDD induction of CYP1A1, suggesting that pRb may be a general AhR coactivator.
Footnotes
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Send reprint requests to: Cornelis J. Elferink, Ph.D., Institute of Chemical Toxicology, 2727 Second Ave., Room 4000, MCHT, Wayne State University, Detroit, MI 48201. E-mail:cornelis_elferink{at}wayne.edu
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↵1 Current address: Laboratory of Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
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Supported by the National Institute of Environmental Health Sciences (NIEHS) Grant R29-ES07800 and, in part, by NIEHS Center Grant ES06639.
- Abbreviations:
- AhR
- aryl hydrocarbon receptor
- bHLH
- basic helix-loop-helix
- TCDD
- 2,3,7,8-tetrachlorodibenzo-p-dioxin
- PAS
- Per-Arnt-Sim (periodicity/aryl hydrocarbon receptor nuclear translocator/simple-minded)
- hsp90
- 90-kDa heat shock protein
- Arnt
- aryl hydrocarbon receptor nuclear translocator
- pRb
- retinoblastoma protein
- CDK
- cyclin-dependent kinase
- bp
- base pair(s)
- PCR
- polymerase chain reaction
- GFP
- green fluorescent protein
- WT
- wild-type
- RT
- reverse transcription (or transcriptase)
- Me2SO
- dimethyl sulfoxide
- TAD
- transactivation domain
- EMSA
- electrophoretic mobility shift assay
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- Received May 25, 2000.
- Accepted December 1, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
