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Originally published In Press as doi:10.1074/jbc.M309646200 on October 21, 2003

J. Biol. Chem., Vol. 279, Issue 2, 1281-1290, January 9, 2004
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Sphingosine-phosphate Lyase Enhances Stress-induced Ceramide Generation and Apoptosis*

Ulrike Reiss{ddagger}, Babak Oskouian{ddagger}, Jianhui Zhou{ddagger}, Vinita Gupta{ddagger}, Prathap Sooriyakumaran{ddagger}, Samuel Kelly§, Elaine Wang§, Alfred H. Merrill, Jr.§, and Julie D. Saba{ddagger}

From the {ddagger}Children's Hospital Oakland Research Institute, Oakland, California 94609-1673 and the §Georgia Institute of Technology, School of Biology, Atlanta, Georgia 30332-0230

Sphingosine-1-phosphate lyase is a widely expressed enzyme that catalyzes the essentially irreversible cleavage of the signaling molecule sphingosine 1-phosphate. To investigate whether sphingosine-1-phosphate lyase influences mammalian cell fate decisions, a recombinant human sphingosine-1-phosphate lyase fused to green fluorescent protein was expressed in HEK293 cells. The recombinant enzyme was active, localized to the endoplasmic reticulum, and reduced baseline sphingosine and sphingosine 1-phosphate levels. Stable overexpression led to diminished viability under stress, which was attributed to an increase in apoptosis and was reversible in a dose-dependent manner by exogenous sphingosine 1-phosphate. In contrast to sphingosine 1-phosphate, the products of the lyase reaction had no effect on apoptosis. Lyase enzymatic activity was required to potentiate apoptosis, because cells expressing a catalytically inactive enzyme behaved like controls. Stress increased the amounts of long- and very long-chain ceramides in HEK293 cells, and this was enhanced in cells overexpressing wild type but not catalytically inactive lyase. The ceramide increases appeared to be required for apoptosis, because inhibition of ceramide synthase with fumonisin B1 decreased apoptosis in lyase-overexpressing cells. Thus, sphingosine-1-phosphate lyase overexpression in HEK293 cells decreases sphingosine and sphingosine 1-phosphate amounts but elevates stress-induced ceramide generation and apoptosis. This identifies sphingosine-1-phosphate lyase as a dual modulator of sphingosine 1-phosphate and ceramide metabolism as well as a regulator of cell fate decisions and, hence, a potential target for diseases with an imbalance in these biomodulators, such as cancer.

Received for publication, September 2, 2003 , and in revised form, October 16, 2003.

* This work was supported by National Institutes of Health Grants 1R01CA77528 and 1R01GM066954 (to J. D. S.), 5-T32-HL07951-03 (to U. R.), and 5R01GM046368 (to A. H. M.). 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: Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland, CA 94609-1673. Tel.: 510-450-7690; Fax: 510-450-7910; e-mail: jsaba{at}chori.org.


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