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J. Biol. Chem., Vol. 279, Issue 49, 50700-50709, December 3, 2004

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Inhibition of HMC-1 Mast Cell Proliferation by Vitamin E

INVOLVEMENT OF THE PROTEIN KINASE B PATHWAY^*

Petra Kempná, Elke Reiter, Michel Arock, Angelo Azzi, and Jean-Marc Zingg¶

From the Institute of Biochemistry and Molecular Biology, University of Bern, Bühlstrasse 28, 3012 Bern, Switzerland and the CNRS Unit FRE 2444, Faculty of Pharmacy, 4 Ave de l'Observatoire, 75006 Paris, France

The effects of four natural tocopherols on the proliferation and signaling pathways were examined in the human mastocytoma cell line (HMC-1). The four tocopherols inhibited HMC-1 cell proliferation with different potency ( > = > ). Growth inhibition correlated with the reduction of PKB (protein kinase B) phosphorylation by the different tocopherols. The reduction of PKB phosphorylation led to a decrease of its activity, as judged from a parallel reduction of GSK/ phosphorylation. The translocation of PKB to the membrane, as a response to receptor stimulation by NGF, is also prevented by treatment with tocopherols. In the presence of PKC or PP2A inhibitors, the reduction of PKB phosphorylation by tocopherols was still observed, thus excluding the direct involvement of these enzymes. Other pathways, such as the Ras-stimulated ERK1/2 (extracellular signal responsive kinase) pathway, were not affected by tocopherol treatment. The tocopherols did not significantly change oxidative stress in HMC-1 cells, suggesting that the observed effects are not the result of a general reduction of oxidative stress. Thus, the tocopherols interfere with PKB phosphorylation and reduce proliferation of HMC-1 cells, possibly by modulating either phosphatidylinositol 3-kinase, a kinase phosphorylating PKB (PDK1/2), or a phosphatase that dephosphorylates it. Inhibition of proliferation and PKB signaling in HMC-1 cells by vitamin E suggests a role in preventing diseases with mast cell involvement, such as allergies, atherosclerosis, and tumorigenesis.

Received for publication, September 20, 2004

^* This work was supported by the Swiss National Science Foundation and the Foundation for Nutrition Research in Switzerland. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Institut für Biochemie und Molekularbiologie, Universität Bern, Bühlstrasse 28, CH-3012 Bern, Switzerland. Tel.: 41-31-631-41-18; Fax: 41-31-631-37-37; E-mail: zingg{at}mci.unibe.ch.

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