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Vol. 57, Issue 5, 1056-1063, May 2000
Laboratory of Metabolism (G.E., P.F.-S., G.-Y.K., K.S.L., F.J.G.)
and Gene Response Section (M.S.S., A.J.F.), Division of Basic Sciences,
National Cancer Institute, Bethesda, Maryland
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-
(TGF-), 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-3 also resulted
in down-regulation of both Cdc2 and Plk. Thus, overproduction of
TGF- 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- production, leading
to an alteration in cell cycle control.
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