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Blood, 16 July 2009, Vol. 114, No. 3, pp. 572-579. Prepublished online as a Blood First Edition Paper on May 13, 2009; DOI 10.1182/blood-2009-02-204230. This Article Full Text Full Text (PDF) Supplemental Tables and Figures All Versions of this Article: blood-2009-02-204230v1 114/3/572    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 Ueffing, N. Articles by Schwerk, C. PubMed PubMed Citation Articles by Ueffing, N. Articles by Schwerk, C. Related Collections Immunobiology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY A single nucleotide polymorphism determines protein isoform production of the human c-FLIP protein Nana Ueffing1,2,*, Kusum K. Singh1,*, Andrea Christians3, Christoph Thorns4, Alfred C. Feller4, Florian Nagl5, Falko Fend5, Sebastian Heikaus6, Alexander Marx7, Rainer B. Zotz8, Joachim Brade9, Wolfgang A. Schulz10, Klaus Schulze-Osthoff1,11,, Ingo Schmitz1,2,, and Christian Schwerk1,12, 1 Institute of Molecular Medicine and 2 Institute of Medical Microbiology and Hospital Hygiene, University of Duesseldorf, Duesseldorf; 3 Institute for Pathology, Remscheid; 4 Institute of Pathology, University of Luebeck, Luebeck; 5 Department of Pathology, University of Tuebingen, Tuebingen; 6 Institute of Pathology, University of Duesseldorf, Duesseldorf; 7 Department of Pathology, Mannheim Medical Faculty, University of Heidelberg, Mannheim; 8 Department of Hemostasis and Transfusion Medicine, University of Duesseldorf, Duesseldorf; 9 Department of Statistics, Mannheim Medical Faculty, University of Heidelberg, Mannheim; 10 Department of Urology, Urological Hospital, University of Duesseldorf, Duesseldorf; 11 Interfaculty Institute for Biochemistry, University of Tuebingen, Tuebingen; and 12 Childrens Hospital, Mannheim Medical Faculty, University of Heidelberg, Mannheim, Germany The cellular FLICE-inhibitory protein (c-FLIP) is a modulator of death receptor-mediated apoptosis and plays a major role in T- and B-cell homeostasis. Three different isoforms have been described on the protein level, including the long form c-FLIPL as well as 2 short forms, c-FLIPS and the recently identified c-FLIPR. The mechanisms controlling c-FLIP isoform production are largely unknown. Here, we identified by sequence comparison in several mammals that c-FLIPR and not the widely studied c-FLIPS is the evolutionary ancestral short c-FLIP protein. Unexpectedly, the decision for production of either c-FLIPS or c-FLIPR in humans is defined by a single nucleotide polymorphism in a 3' splice site of the c-FLIP gene (rs10190751A/G). Whereas an intact splice site directs production of c-FLIPS, the splice-dead variant causes production of c-FLIPR. Interestingly, due to differences in protein translation rates, higher amounts of c-FLIPS protein compared with c-FLIPR are produced. Investigation of diverse human cell lines points to an increased frequency of c-FLIPR in transformed B-cell lines. A comparison of 183 patients with follicular lymphoma and 233 population controls revealed an increased lymphoma risk associated with the rs10190751 A genotype causing c-FLIPR expression. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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