Altered Cell Cycle Control at the G2/M Phases in Aryl Hydrocarbon Receptor-Null Embryo Fibroblast
- Guillermo Elizondo1,1,
- Pedro Fernandez-Salguero2,1,
- M. Saeed Sheikh2,
- Geum-Yi Kim1,
- Albert J. Fornace2,
- Kyung S. Lee1 and
- Frank J. Gonzalez1
- 1Laboratory of Metabolism (G.E., P.F.-S., G.-Y.K., K.S.L., F.J.G.) and 2Gene Response Section (M.S.S., A.J.F.), Division of Basic Sciences, National Cancer Institute, Bethesda, Maryland
Abstract
The aryl hydrocarbon receptor (AHR) is known to mediate the toxic and carcinogenic effects of polycyclic aromatic hydrocarbons and dioxins. High-affinity AHR ligands, such as 2,3,7,8-tetrachlorodibenzeno-p-dioxin, have been shown to modify cell proliferation and differentiation. However, the mechanisms by which AHR affects cell proliferation and differentiation are not fully understood. To investigate the role of AHR in cell proliferation, mouse embryonic fibroblasts (MEFs) derived from AHR-null mice were obtained and characterized. Compared with wild-type MEFs, AHR-null cells exhibited a lower proliferation rate with an accumulation of 4N DNA content and increased apoptosis. The expression levels of Cdc2 and Plk, two kinases important for G2/M phase of cell cycle, were down-regulated in AHR-null MEFs. In contrast, transforming growth factor-β (TGF-β), a proliferation inhibitor in several cell lines, was present at high levels in conditioned medium from AHR-null MEFs. Concomitant with G2/M cell accumulation, treatment of wild-type MEFs with TGF-β3 also resulted in down-regulation of both Cdc2 and Plk. Thus, overproduction of TGF-β in AHR-deficient cells appears to be the primary factor that causes low proliferation rates and increased apoptosis. Taken together, these results suggest that AHR influences TGF-β production, leading to an alteration in cell cycle control.
Footnotes
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Send reprint requests to: Dr. Frank J. Gonzalez, Laboratory of Metabolism, National Cancer Institute, Building 37, Room 3E24, Bethesda, MD 20892. E-mail:fjgonz{at}helix.nih.gov
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↵1 Present address: Departado Farmacologia y Toxicologia, Instituto Politecnico Nacional, San Pedro Zacatenco, Mexico DF CP 07730.
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↵2 Laboratorio de Bioquimica y Biologia Molecular, Facultad de Ciencias, Universidad de Extremadura, 06071 Badajoz, Spain.
- Abbreviations:
- AHR
- aryl hydrocarbon receptor
- HAH
- halogenated aromatic hydrocarbon
- MEF
- mouse embryonic fibroblast
- DMEM
- Dulbecco's modified Eagle's medium
- DAPI
- 4′-diamino-2-phenylindole
- TCDD
- 2,3,7,8-tetrachlorodibenzeno-p-dioxin
- TGF-β
- transforming growth factor-β
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- Received September 15, 1999.
- Accepted January 5, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
