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Carcinogenesis Advance Access published online on March 28, 2008
Carcinogenesis, doi:10.1093/carcin/bgn084
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Nickel compounds induce phosphorylation of histone H3 at serine 10 by activating JNK-MAPK pathway

Qingdong Ke, Qin Li, Thomas P. Ellen, Hong Sun and Max Costa*

Department of Environmental Medicine, New York University School of Medicine, 550 First Ave., New York, NY 10016

* Corresponding author mail address: Dr. Max Costa, Department of Environmental Medicine New York University School of Medicine, 550 First Ave., New York, NY 10016, Tel: 845-731-3515, Fax: 845-351-2118, E-mail: costam{at}env.med.nyu.edu

Nickel is a known carcinogen, although the mechanism of its carcinogenicity is not clear. Here, we provide evidence that nickel can induce phosphorylation of histone H3 at its serine 10 residue in a JNK/SAPK-dependent manner. Nickel induces the phosphorylation of c-Jun amino-terminal kinase (JNK), with no effect on the phosphorylation states of the ERK or p38 MAP kinases. An inhibitor of JNK eliminated the nickel-initiated JNK-mediated induction of histone H3 phosphorylation at serine 10, while inhibitors specific for ERK or p38 kinases had no effect on the phosphorylation levels of histone H3 at serine 10 (P-H3S10) in nickel-treated cells. A complete loss of Ni ion induced phosphorylation of H3S10 was observed when JNK was specifically knocked down with RNAi. These results are the first to show the specific JNK-mediated phosphorylation of histone H3 at its serine 10 residue. We show that addition of nickel to an in vitro P-H3S10 dephosphorylation reaction does not change the loss of phosphorylation in the reaction, supporting the notion that nickel causes H3S10 phosphorylation via the JNK/SAPK kinase pathway. It is likely that modification of histone H3 at serine 10 is one of a growing number of epigenetic changes believed to be involved in the carcinogenesis caused by nickel

Key Words: nickel • histone phosphorylation • mitogen-activated protein kinase (MAPK) • c-Jun amino-terminal kinase (JNK) • extracellular signal-regulated kinase (ERK) • p38 • phosphatase

Received October 15, 2007; revised March 8, 2008; accepted March 20, 2008.


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