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J. Biol. Chem., Vol. 283, Issue 39, 26509-26517, September 26, 2008

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Ceramide Generated by Sphingomyelin Hydrolysis and the Salvage Pathway Is Involved in Hypoxia/Reoxygenation-induced Bax Redistribution to Mitochondria in NT-2 Cells^*

Junfei Jin¹, Qi Hou¹, Thomas D. Mullen^¶, Youssef H. Zeidan, Jacek Bielawski, Jacqueline M. Kraveka^||2, Alicja Bielawska, Lina M. Obeid^¶**, Yusuf A. Hannun, and Yi-Te Hsu³

From the Departments of Biochemistry and Molecular Biology, ^¶Medicine, and ^||Pediatrics, Division of Hematology/Oncology, Medical University of South Carolina, Charleston, South Carolina 29425, the Department of Pharmacology, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, China, and the ^**Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina 29401

Ceramide functions as an important second messenger in apoptosis signaling pathways. In this report, we show that treatment of NT-2 neuronal precursor cells with hypoxia/reoxygenation (H/R) resulted in ceramide up-regulation. This elevation in ceramide was primarily due to the actions of acid sphingomyelinase and ceramide synthase LASS 5, demonstrating the action of the salvage pathway. Hypoxia/reoxygenation treatment led to Bax translocation from the cytoplasm to mitochondria and cytochrome c release from mitochondria. Down-regulation of either acid sphingomyelinase or LASS 5-attenuated ceramide accumulation and H/R-induced Bax translocation to mitochondria. Overall, we have demonstrated that ceramide up-regulation following H/R is pertinent to Bax activation to promote cell death.

Received for publication, February 27, 2008 , and in revised form, July 30, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants NS40932 (to Y.-T. H.) and CA97132 (to Y. A. H.). 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.

¹ Both authors contributed equally to this work.

² Recipient of National Institutes of Health Grants K01-CA100767 and P20-RR17677, the Rally Foundation for Childhood Cancer Research, and the Monic Kreber Golf Tournament.

³ To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, Medical University of South Carolina, 173 Ashley Ave., PO Box 250509, Charleston, SC 29425. Fax: 843-792-8565; E-mail: hsuy{at}musc.edu.

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