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Papers In Press, published online ahead of print June 1, 2009
J. Lipid Res., doi:10.1194/jlr.M800666-JLR200

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Journal of Lipid Research, Vol. 50, 1203-1208, June 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

Fatty acid 2-hydroxylase regulates cAMP-induced cell cycle exit in D6P2T Schwannoma cells

Nathan L. Alderson² and Hiroko Hama¹

Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425
² Present address of N. L. Alderson: Department of Surgery, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA 90048.

The online version of this article (available at http://www.jlr.org) contains supplementary data in the form of a table.

Published, JLR Papers in Press, January 23, 2009.

This work was supported by National Institutes of Health Grants RR-17677 and NS-060807.

¹ To whom correspondence should be addressed. e-mail: hama{at}musc.edu

Sphingolipids are ubiquitous components of eukaryotic cells that regulate various cellular functions. In many cell types, a fraction of sphingolipids contain 2-hydroxy fatty acids, produced by fatty acid 2-hydroxylase (FA2H), as the N-acyl chain of ceramide [hydroxyl fatty acid (hFA)-sphingolipids]. FA2H is highly expressed in myelin-forming cells of the nervous system and in epidermal keratinocytes. While hFA-sphingolipids are thought to enhance the physical stability of specialized membranes produced by these cells, physiological significance of hFA-sphingolipids in many other cell types is unknown. In this study, we report novel roles for FA2H and hFA-sphingolipids in the regulation of the cell cycle. Treatment of D6P2T Schwannoma cells with dibutyryl-cAMP (db-cAMP) induced exit from the cell cycle with concomitant upregulation of FA2H. Partial silencing of FA2H in D6P2T cells resulted in 60–70% reduction of hFA-dihydroceramide and hFA-ceramide, with no effect on nonhydroxy dihydroceramide and ceramide. Under these conditions, db-cAMP no longer induced cell cycle exit, and cells continued to grow and divide. Immunoblot analyses revealed that FA2H silencing prevented db-cAMP-induced upregulation of cyclin-dependent kinase inhibitors p21 and p27. These results provide evidence that FA2H is a negative regulator of the cell cycle and facilitates db-cAMP-induced cell cycle exit in D6P2T cells.

Supplementary key words sphingolipid • fatty acid -hydroxylase • hydroxy fatty acids • cell cycle control • cyclin-dependent kinase inhibitor

Abbreviations: CDK, cyclin-dependent kinase; db-cAMP, dibutyryl adenosine 3',5'-cyclic monophosphate; DHC, dihydroceramide; FA2H, fatty acid 2-hydroxylase; hFA, hydroxy fatty acid; shRNA, short hairpin RNA

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