Elizondo G, Fernandez-Salguero P, Sheikh M S, Kim G Y, Fornace A J, Lee K S, Gonzalez F J
Laboratory of Metabolism, Division of Basic Sciences, National Cancer Institute, Bethesda, MD 20892, USA.
Mol Pharmacol. 2000 May;57(5):1056-63.
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 G(2)/M phase of cell cycle, were down-regulated in AHR-null MEFs. In contrast, transforming growth factor-beta (TGF-beta), a proliferation inhibitor in several cell lines, was present at high levels in conditioned medium from AHR-null MEFs. Concomitant with G(2)/M cell accumulation, treatment of wild-type MEFs with TGF-beta3 also resulted in down-regulation of both Cdc2 and Plk. Thus, overproduction of TGF-beta 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-beta production, leading to an alteration in cell cycle control.
已知芳烃受体（AHR）介导多环芳烃和二恶英的毒性和致癌作用。高亲和力的AHR配体，如2,3,7,8-四氯二苯并对二恶英，已被证明可改变细胞增殖和分化。然而，AHR影响细胞增殖和分化的机制尚未完全了解。为了研究AHR在细胞增殖中的作用，我们获取并鉴定了源自AHR基因敲除小鼠的小鼠胚胎成纤维细胞（MEF）。与野生型MEF相比，AHR基因敲除细胞的增殖速率较低，4N DNA含量增加且凋亡增加。细胞周期G(2)/M期重要的两种激酶Cdc2和Plk的表达水平在AHR基因敲除的MEF中下调。相反，转化生长因子-β（TGF-β），一种在几种细胞系中的增殖抑制剂，在AHR基因敲除的MEF的条件培养基中含量很高。与G(2)/M期细胞积累同时发生的是，用TGF-β3处理野生型MEF也导致Cdc2和Plk的下调。因此，AHR缺陷细胞中TGF-β的过量产生似乎是导致低增殖率和凋亡增加的主要因素。综上所述，这些结果表明AHR影响TGF-β的产生，导致细胞周期调控发生改变。
