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Zinc chloride stimulates DNA synthesis of mouse embryonic stem cells: Involvement of PI3K/Akt, MAPKs, and mTOR
Author(s) -
Ryu Jung Min,
Lee Min Young,
Yun Seung Pil,
Han Ho Jae
Publication year - 2009
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.21628
Subject(s) - pi3k/akt/mtor pathway , protein kinase b , wortmannin , kinase , microbiology and biotechnology , cell cycle , cell growth , chemistry , rptor , phosphorylation , signal transduction , biology , cell , biochemistry
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 µM) significantly increased [ 3 H]‐thymidine incorporation after 12 h of treatment. At moderate concentrations (≥4 µM), ZnCl 2 increased cell cycle regulatory protein levels, [ 3 H]‐thymidine incorporation, and total cell numbers, but higher doses of ZnCl 2 (≥200 µM) 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. J. Cell. Physiol. 218: 558–567, 2009. © 2008 Wiley‐Liss, Inc.