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Blood, 15 April 2008, Vol. 111, No. 8, pp. 4365-4374. Prepublished online as a Blood First Edition Paper on February 12, 2008; DOI 10.1182/blood-2007-08-106336. This Article Full Text (PDF) Supplemental Figures and Table All Versions of this Article: blood-2007-08-106336v1 111/8/4365    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Chen, C.-L. Articles by Lin, Y.-S. Search for Related Content PubMed PubMed Citation Articles by Chen, C.-L. Articles by Lin, Y.-S. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted August 9, 2007 Accepted January 27, 2008 Ceramide induces p38 MAPK and JNK activation through a mechanism involving a thioredoxin-interacting protein-mediated pathway Chia-Ling Chen, Chiou-Feng Lin, Wen-Tsan Chang, Wei-Ching Huang, Chiao-Fang Teng, and Yee-Shin Lin* Institute of Basic Medical Sciences, National Cheng Kung University Medical College, Tainan, Taiwan Institute of Clinical Medicine, National Cheng Kung University Medical College, Tainan, Taiwan Department of Biochemistry and Molecular Biology, National Cheng Kung University Medical College, Tainan, Taiwan Department of Microbiology and Immunology, National Cheng Kung University Medical College, Tainan, Taiwan * Corresponding author; email: yslin1{at}mail.ncku.edu.tw. Ceramide, a tumor-suppressor lipid, is generated by sphingomyelin hydrolysis or by de novo synthesis when cells are activated by various stress stimuli as well as when cancer cells are subjected to genotoxic chemotherapy. Ceramide may modulate apoptotic signaling pathways; however, its transcription-dependent effects remain unclear. Our data showed that actinomycin D partially inhibited ceramide-induced apoptosis. Using microarray analysis, we found that ceramide up-regulated a tumor suppressor gene thioredoxin-interacting protein (Txnip). Similarly, the chemotherapeutic agent etoposide induced Txnip expression en route to apoptosis, which was blocked by inhibitors of ceramide production. Txnip co-localized with thioredoxin and reduced its activity, which caused dissociation of thioredoxin from ASK1. Cells expressing ASK1 siRNA were more resistant to ceramide-induced apoptosis. Ceramide caused ASK1-regulated p38 MAPK and JNK activation, as well as activation of the ER stress cascade, and pharmacologic or siRNA-mediated inhibition of p38 MAPK or JNK partially reduced ceramide-induced mitochondria-mediated apoptosis. Furthermore, ceramide-induced ASK1, p38 and JNK phosphorylation and cell apoptosis were inhibited by Txnip siRNA transfection. Taken together, we show that ceramide exhibits a mechanism of transcriptional regulation involving up-regulation of Txnip expression, also induced by etoposide, which results in ASK1 activation, ER stress, and p38 and JNK phosphorylation, all leading to apoptosis. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: C. E. Balatoni, D. W. Dawson, J. Suh, M. H. Sherman, G. Sanders, J. S. Hong, M. J. Frank, C. S. Malone, J. W. Said, and M. A. Teitell Epigenetic Silencing of Stk39 in B-Cell Lymphoma Inhibits Apoptosis from Genotoxic Stress Am. J. Pathol., October 1, 2009; 175(4): 1653 - 1661. [Abstract] [Full Text] [PDF] C. Zang, H. Liu, J. Bertz, K. Possinger, H. P. Koeffler, E. Elstner, and J. Eucker Induction of endoplasmic reticulum stress response by TZD18, a novel dual ligand for peroxisome proliferator-activated receptor {alpha}/{gamma}, in human breast cancer cells Mol. Cancer Ther., August 1, 2009; 8(8): 2296 - 2307. [Abstract] [Full Text] [PDF] B.-C. Chen, H.-M. Chang, M.-J. Hsu, C.-M. Shih, Y.-H. Chiu, W.-T. Chiu, and C.-H. Lin Peptidoglycan Induces Cyclooxygenase-2 Expression in Macrophages by Activating the Neutral Sphingomyelinase-Ceramide Pathway J. Biol. Chem., July 31, 2009; 284(31): 20562 - 20573. [Abstract] [Full Text] [PDF] F.-X. Yu, S.-R. Goh, R.-P. Dai, and Y. Luo Adenosine-Containing Molecules Amplify Glucose Signaling and Enhance Txnip Expression Mol. Endocrinol., June 1, 2009; 23(6): 932 - 942. [Abstract] [Full Text] [PDF] E. Masson, S. Koren, F. Razik, H. Goldberg, E. P. Kwan, L. Sheu, H. Y. Gaisano, and I. G. Fantus High {beta}-cell mass prevents streptozotocin-induced diabetes in thioredoxin-interacting protein-deficient mice Am J Physiol Endocrinol Metab, June 1, 2009; 296(6): E1251 - E1261. [Abstract] [Full Text] [PDF] K. Kitatani, K. Sheldon, V. Anelli, R. W. Jenkins, Y. Sun, G. A. Grabowski, L. M. Obeid, and Y. A. Hannun Acid {beta}-Glucosidase 1 Counteracts p38{delta}-dependent Induction of Interleukin-6: POSSIBLE ROLE FOR CERAMIDE AS AN ANTI-INFLAMMATORY LIPID J. Biol. Chem., May 8, 2009; 284(19): 12979 - 12988. [Abstract] [Full Text] [PDF]

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