Aryl Hydrocarbon Receptor Is Required for p300-Mediated Induction of DNA Synthesis by Adenovirus E1A
- 1Laboratory of Metabolism, National Cancer Institute, National Institute of Health, Bethesda, Maryland (M.T., G.E., S.T., F.J.G.); and2Department of Pharmaceutical Sciences, National Institute of Public Health, Minato-ku, Tokyo, Japan (M.T., M.F.)
Abstract
The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates the biological responses to environmental contaminants such as 2,3,7,8-tetrachlorodibenzo-p-dioxin. Embryonic fibroblast (EF) isolated from AHR-null mice exhibited slow cell growth compared with wild-type EF. Reintroduction of AHR into AHR-null EF increased cell growth, suggesting that AHR is involved in cell cycle control. The role of the AHR in cell cycle control was examined using the adenovirus oncoprotein E1A. EF, derived from wild-type and AHR-null mice, were transfected with two mutant E1A expression plasmids that inactivate either p300/CBP or retinoblastoma protein (pRb). Although DNA synthesis of wild-type EF was induced by both E1A mutants, DNA synthesis in the AHR-null EF was induced only by the mutant that binds pRb, not by the mutant to p300/CBP. These data show that both pRb and p300/CBP were the target of E1A-induced DNA synthesis in wild-type EF. In AHR-null mice, however, only pRb was the target of E1A-induced DNA synthesis and p300/CBP cannot be inactivated by E1A in the absence of AHR. Immunoprecipitation revealed that AHR directly bound to p300, thus suggesting the intriguing possibility that AHR is involved in control of the cell cycle via interaction with p300.
Footnotes
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Send reprint requests to: Dr. Frank J. Gonzalez, Laboratory of Molecular Carcinogenesis, National Cancer Institute, 9000 Rockville Pike, Bldg. 37, Room 3E24, Bethesda, MD 20892-0001.
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M.T. was supported by a grant from the Japan Health Science Foundation.
- Abbreviations:
- AHR
- aryl hydrocarbon receptor
- TCDD
- 2,3,7,8-tetrachlorodibenzo-p-dioxin
- ARNT
- AHR nuclear translocator
- XRE
- xenobiotic response element
- EF
- embryonic fibroblast
- CBP
- cAMP response element-binding protein
- pRb
- retinoblastoma protein
- DMEM
- Dulbecco's modified Eagle's medium
- FBS
- fetal bovine serum
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- Received February 22, 2000.
- Accepted June 23, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
