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Zinc chloride stimulates DNA synthesis of mouse embryonic stem cells: involvement of PI3K/Akt, MAPKs, and mTOR.
J Cell Physiol. 2009 Mar; 218(3):558-67.JC

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.

Authors+Show Affiliations

Department of Veterinary Physiology, College of Veterinary Medicine, Biotherapy Human Resources Center (BK21), Chonnam National University, Gwangju, Korea.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18988195

Citation

Ryu, Jung Min, et al. "Zinc Chloride Stimulates DNA Synthesis of Mouse Embryonic Stem Cells: Involvement of PI3K/Akt, MAPKs, and MTOR." Journal of Cellular Physiology, vol. 218, no. 3, 2009, pp. 558-67.
Ryu JM, Lee MY, Yun SP, et al. Zinc chloride stimulates DNA synthesis of mouse embryonic stem cells: involvement of PI3K/Akt, MAPKs, and mTOR. J Cell Physiol. 2009;218(3):558-67.
Ryu, J. M., Lee, M. Y., Yun, S. P., & Han, H. J. (2009). Zinc chloride stimulates DNA synthesis of mouse embryonic stem cells: involvement of PI3K/Akt, MAPKs, and mTOR. Journal of Cellular Physiology, 218(3), 558-67. https://doi.org/10.1002/jcp.21628
Ryu JM, et al. Zinc Chloride Stimulates DNA Synthesis of Mouse Embryonic Stem Cells: Involvement of PI3K/Akt, MAPKs, and MTOR. J Cell Physiol. 2009;218(3):558-67. PubMed PMID: 18988195.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Zinc chloride stimulates DNA synthesis of mouse embryonic stem cells: involvement of PI3K/Akt, MAPKs, and mTOR. AU - Ryu,Jung Min, AU - Lee,Min Young, AU - Yun,Seung Pil, AU - Han,Ho Jae, PY - 2008/11/7/pubmed PY - 2009/1/14/medline PY - 2008/11/7/entrez SP - 558 EP - 67 JF - Journal of cellular physiology JO - J Cell Physiol VL - 218 IS - 3 N2 - 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. SN - 1097-4652 UR - https://www.unboundmedicine.com/medline/citation/18988195/Zinc_chloride_stimulates_DNA_synthesis_of_mouse_embryonic_stem_cells:_involvement_of_PI3K/Akt_MAPKs_and_mTOR_ L2 - https://doi.org/10.1002/jcp.21628 DB - PRIME DP - Unbound Medicine ER -