Induction of the cell cycle regulatory gene p21 (Waf1, Cip1) following methylmercury exposure in vitro and in vivo
Induction of the cell cycle regulatory gene p21 (Waf1, Cip1) following methylmercury exposure in vitro and in vivo
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DOI：
10.1006/taap.1999.8685
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发表时间：
1999-06-15
影响因子：
3.8
通讯作者：
Faustman, EM
中科院分区：
文献类型：
--
作者：
Ou, YC;Thompson, SA;Faustman, EM
甲基汞（MeHg）被认为是一种严重的环境危害，特别是对神经系统的发育。为了研究甲基汞抑制细胞周期的分子机制，我们评估了甲基汞暴露后原代胚胎细胞和成年小鼠中p21（Waf 1，Cip 1）的参与，p21是一种细胞周期调控基因，参与细胞周期停滞的G（1）和G（2）期。先前的文献支持p21表达增加与软骨细胞分化的关联。为了支持这一发现，我们观察到在肢芽（LB），但不是中脑中枢神经系统（CNS）细胞分化过程中p21的表达增加。胚胎LB和中枢神经系统细胞对甲基汞暴露的p21 mRNA的浓度依赖性增加。在成人平行研究中，C57 BL/6雌性小鼠通过饮用水长期暴露于10 ppm甲基汞，持续4周。虽然Gadd 45、Gadd 153和γ-谷氨酰半胱氨酸合成酶催化亚基的诱导有限或不存在，但在大多数显示出甲基汞诱导的行为毒性（如多动和震颤）的动物中，p21在脑、肾和肝组织中被显著诱导。此外，p21 mRNA的诱导伴随着p21蛋白水平的增加。结果表明，细胞周期调控基因的激活可能是甲基汞干扰成年和发育中生物体细胞周期的机制之一。继续研究细胞周期抑制的分子机制可能会导致利用这一机制信息来表征体内甲基汞暴露的影响。(C)北京：科学出版社.
Methylmercury (MeHg) is recognized as a significant environmental hazard, particularly to the development of the nervous system. To study the molecular mechanisms underlying cell cycle inhibition by MeHg, we assessed the involvement of p21 (Waf1, Cip1), a cell cycle regulatory gene implicated in the G(1) and G(2) phases of cell cycle arrest, in primary embryonic cells and adult mice following MeHg exposure. Previous literature has supported the association of increased p21 expression with chondrocyte differentiation. In support of this finding, we observed an increasing p21 expression during limb bud (LB), but not midbrain central nervous system (CNS) cell differentiation. Both embryonic LB and CNS cells responded to MeHg exposure with a concentration-dependent increase in p21 mRNA. In the parallel adult study, C57BL/6 female mice were chronically exposed to 10 ppm MeHg via drinking water for 4 weeks. While there was limited or absent induction of Gadd45, Gadd153, and the gamma-glutamylcysteine synthetase catalytic subunit, p21 was markedly induced in the brain, kidney, and liver tissues in most of the animals that showed MeHg-induced behavioral toxicity such as hyperactivity and tremor. Furthermore, the induction of p21 mRNA was accompanied by an increase in p21 protein level. The results indicate that the activation of cell cycle regulatory genes may be one mechanism by which MeHg interferes with the cell cycle in adult and developing organisms. Continued examination of the molecular mechanisms underlying cell cycle inhibition may potentially lead to utilization of this mechanistic information to characterize the effects of MeHg exposure in vivo. (C) 1999 Academic Press.