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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 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 Citation Map 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 CrossRef Google Scholar Articles by Chen, C.-L. Articles by Lin, Y.-S. PubMed PubMed Citation Articles by Chen, C.-L. Articles by Lin, Y.-S. Related Collections Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Ceramide induces p38 MAPK and JNK activation through a mechanism involving a thioredoxin-interacting protein-mediated pathway Chia-Ling Chen1, Chiou-Feng Lin2, Wen-Tsan Chang3, Wei-Ching Huang1, Chiao-Fang Teng3, and Yee-Shin Lin4,5 1 Institute of Basic Medical Sciences; 2 Institute of Clinical Medicine; 3 Department of Biochemistry and Molecular Biology; 4 Department of Microbiology and Immunology; and 5 Center for Gene Regulation and Signal Transduction Research, National Cheng Kung University Medical College, Tainan, Taiwan 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 called 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 colocalized with thioredoxin and reduced its activity, which caused dissociation of thioredoxin from apoptosis signal-regulating kinase 1 (ASK1). Cells expressing ASK1 siRNA were more resistant to ceramide-induced apoptosis. Ceramide caused ASK1-regulated p38 mitogen-activated protein kinase (MAPK) and JNK activation, as well as activation of the endoplasmic reticulum (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?

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