Altered cell cycle control at the G(2)/M phases in aryl hydrocarbon receptor-null embryo fibroblast

The aryl hydrocarbon receptor (AHR) is known to mediate the toxic and carci nogenic effects of polycyclic aromatic hydrocarbons and dioxins. High-affin ity AHR ligands, such as 2,3,7,8-tetrachlorodibenzeno-p-dioxin, have been s hown to modify cell proliferation and differentiation. However, the mechani sms by which AHR affects cell proliferation and differentiation are not ful ly understood. To investigate the role of AHR in cell proliferation, mouse embryonic fibroblasts (MEFs) derived from AHR-null mice were obtained and c haracterized. Compared with wild-type MEFs, AHR-null cells exhibited a lowe r proliferation rate with an accumulation of 4N DNA content and increased a poptosis. The expression levels of Cdc2 and Plk, two kinases important for G(2)/M phase of cell cycle, were down-regulated in AHR-null MEFs. In contra st, transforming growth factor-beta (TGF-beta), a proliferation inhibitor i n several cell lines, was present at high levels in conditioned medium from AHR-null MEFs. Concomitant with G(2)/M cell accumulation, treatment of wil d-type MEFs with TGF-beta 3 also resulted in down-regulation of both Cdc2 a nd Plk. Thus, overproduction of TGF-beta in AHR-deficient cells appears to be the primary factor that causes low proliferation rates and increased apo ptosis. Taken together, these results suggest that AHR influences TGF-beta production, leading to an alteration in cell cycle control.