APE1/Ref-1 prevents oxidative inactivation of ERK for G(1)-to-S progression following lead acetate exposure

作者：Wang Yi Ting; Tzeng Der Wan; Wang Chun Yu; Hong Jing Yin; Yang Jia Ling^*

来源：Toxicology, 2013, 305: 120-129.

DOI：10.1016/j.tox.2013.01.010

• APE1
• ERK
• Heavy metal
• Oxidation
• Cyclin D1

Apurinic/apyrimidinic endonuclease 1 (APE1)/redox effector factor-1 is a multifunctional enzyme involved in DNA base excision repair and protein redox regulation. Previously, we have showed that lead acetate (Pb) elicits EGFR activation to initiate the SFK/PKC alpha/Ras/Raf-1/MKK1/2/ERK signaling cascade functioning against genotoxicity. Here, we explore whether APE1 and reactive oxygen species (ROS) affect ERK signaling and cell cycle progression following Pb exposure. We found that Pb induced APE1 expression and ROS generation in CL3 human lung cancer cells. The Pb-elicited ROS levels and cytotoxicity were further enhanced by introducing small interfering RNA specific for APE1 (siAPE1). E3330, an inhibitor of APE1 redox activity, also augmented the ROS levels and cytotoxicity in Pb-treated cells. Intriguingly, the capability of Pb to activate ERK was abolished under siAPE1 or E3330 co-treatments; conversely, forced expression of APE1 up-regulated the ERK activation by Pb or serum in both Cys65-redox activity dependent and independent manners. Moreover, APE1 formed complex with ERK2, and its redox activity could rescue ERIC oxidative inactivation. APE1 redox activity also facilitated the Cyclin D1 expression and G(1)-to-S progression following Pb exposure. In summary, the results indicate that APE1 is a direct redox regulator of ERIC for maintaining the kinase activity to promote cell proliferation.

• 出版日期2013-3-8
• 单位清华大学