Extracellular signal-regulated kinase-signaling-dependent G2/M arrest and cell death in murine macrophages by cadmium
Extracellular signal-regulated kinase-signaling-dependent G2/M arrest and cell death in murine macrophages by cadmium
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DOI：
10.1897/04-503r3.1
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发表时间：
2005-12-01
影响因子：
4.1
通讯作者：
Sharma, RP
中科院分区：
文献类型：
--
作者：
Kim, J;Kim, SH;Sharma, RP
镉是一种非必需的重金属，也是众所周知的持久性环境污染物。它会引起各种毒性作用，包括免疫毒性。其细胞效应的确切机制仍不清楚。细胞周期调控是调节细胞死亡的一个重要因素：然而，镉介导的细胞周期停滞导致小鼠巨噬细胞死亡的研究尚未见报道。20mU M镉可诱导培养24 h的小鼠巨噬细胞(J774A.1)凋亡和坏死性死亡，20 mU M镉可使巨噬细胞(J774A.1)重新进入G0/G1期，24 h后G2/M期细胞数增加，细胞外信号调节激酶(ERK)的磷酸化与细胞周期蛋白依赖性激酶抑制因子p21(WAF1/CIP1)的诱导相关。PD98059抑制ERK激活导致G0/G1期停滞，并部分释放镉诱导的G2/M期停滞。PD98059抑制ERK磷酸化可显著减轻镉诱导的细胞死亡，但不能阻止caspase-3的激活和DNA片段化。镉诱导的ERK信号转导导致J774A.1细胞的坏死而不是凋亡。活性氧(ROS)清除剂N-乙酰半胱氨酸可减少镉诱导的ERK激活和细胞死亡，提示镉诱导ROS-ERK-p21(WAF1/CIP1)信号通路，导致G2/M期停滞和细胞死亡。这些发现可能对进一步了解镉毒性的细胞机制提供信息，以客观地评估这种金属的风险。
Cadmium is a nonessential heavy metal and a well-known persistent environmental pollutant. It causes a variety of toxic effects, including immunotoxicity. The exact mechanism of its cellular effects still is unclear. Cell-cycle regulation is an important factor that modulates cell death: however, cadmium-mediated cell-cycle arrest leading to cell death in murine macrophages has not been investigated. Cadmium at 20 mu M induced both apoptotic and necrotic death in murine macrophage (J774A.1) cultures at 24 h. Cadmium at 20 mu M triggered re-entry of G0/G1 to the next phase and increased the number of cells in the G2/M phase at 24 h. Phosphorylation of extracellular signal-regulated kinase (ERK) correlated with the cyclin-dependent kinase inhibitor p21(WAF1/CIP1) induction. Inhibition of ERK activation by PD98059 resulted in G0/G1 arrest and partially released the cadmium-mediated G2/M arrest. Inhibition of ERK phosphorylation by PD98059 strongly attenuated cadmium-induced necrotic cell death, but did not prevent caspase-3 activation and DNA fragmentation. Necrosis rather than apoptosis was caused by cadmium-induced ERK signaling in J774A.1 cells. A scavenger of reactive oxygen species (ROS), N-acetylcystein, decreased cadinium-induced ERK activation and necrotic cell death, Suggesting that cadmium induces the ROS-ERK-p21(WAF1/CIP1) signaling pathway, leading to G2/ M arrest and cell death. These findings may be important in further understanding the cellular mechanisms of cadmium toxicity to provide information to assess objectively risk for this metal.