Zinc chloride stimulates DNA synthesis of mouse embryonic stem cells: Involvement of PI3K/Akt, MAPKs, and mTOR

Abstract

Although zinc is one of the most important trace elements in the body, the mechanisms underlying zinc-induced cell proliferation have yet to be unraveled. Thus, we investigated the effect of zinc chloride (ZnCl(2)) on mouse embryonic stem (ES) cell proliferation and related signaling pathways. ZnCl(2) (40 microM) significantly increased [(3)H]-thymidine incorporation after 12 h of treatment. At moderate concentrations (> or =4 microM), ZnCl(2) increased cell cycle regulatory protein levels, [(3)H]-thymidine incorporation, and total cell numbers, but higher doses of ZnCl(2) (> or =200 microM) blocked this proliferative effect. ZnCl(2) induced the phosphorylation of Akt, c-Jun N-terminal kinases/stress-activated protein kinases (JNK/SAPK), p44/42 MAPKs, and mammalian target of rapamycin (mTOR) in a time-dependent manner. Pretreatment of LY 294002 (a PI3K inhibitor, 10(-6) M), wortmannin (a PI3K inhibitor, 10(-7) M), or an Akt inhibitor (10(-5) M), which inhibited the activation of JNK/SAPK and p44/42 MAPKs, blocked the ZnCl(2)-induced expression of cyclins and cyclin-dependent kinases (CDKs). Furthermore, pretreatment with PD 98059 (a p44/42 inhibitor, 10(-5) M) or SP 600125 (a JNK inhibitor, 10(-6) M) inhibited ZnCl(2)-induced activation of mTOR, p70S6K, and 4E-BP1. In addition, rapamycin (an mTOR inhibitor, 10(-8) M) blocked the ZnCl(2)-induced increase in [(3)H]-thymidine incorporation and cell cycle regulatory protein expression. In conclusion, ZnCl(2) stimulated ES cell proliferation through the PI3K/Akt, p44/42 MAPKs, JNK/SAPK, and mTOR signal pathways.

JNK-Induced Apoptosis, Compensatory Growth, and Cancer Stem Cells

“…In testing the toxicity of the carcinogenic metal chromium [Cr(VI)], Xia and associates demonstrated that JNKs protect mESCs from Cr(VI)-induced cytotoxicity and suppress the differentiation of mESCs or the derived embryonic bodies (EBs) (84). Similarly, JNK signaling appears to be important for the proliferation of mESCs by collaborating with the Akt-mTOR pathway in response to zinc stimulation (85). Furthermore, in a recent study to determine how an essential amino acid, L-threonine, regulates mESCs, Ryu and Han showed that JNK is one of the key kinases necessary for the self-renewal and proliferation of mESCs (86).…”

Graphene oxide and reduced graphene oxide induced neural pheochromocytoma-derived PC12 cell lines apoptosis and cell cycle alterations via the ERK signaling pathways

“…ERK appears to be required for many cells to pass the G1 restriction point and enter the S phase. 36 Several studies have indicated that nanomaterials trigger specific biochemical and biological responses and that these toxic effects are caused by the generation of ROS, which likely induces apoptosis and other signaling pathways such as ERK and AKT (also named PKB). [37][38][39] We hypothesized that GO and rGO induced cell cycle alterations via activation of the ERK signaling pathway.…”

Comparison of inhibitory activities of zinc oxide ultrafine and fine particulates on IgE-induced mast cell activation

“…acts as a PI3K activator. For example, zinc chloride induced the phosphorylation of Akt (Ryu et al 2009). The activation of the PI3K pathway following the intracellular rise of Zn 2?…”