A single nucleotide polymorphism determines protein isoform production of the human c-FLIP protein
| Autor: | Ingo Schmitz, Klaus Schulze-Osthoff, Kusum Kumari Singh, Sebastian Heikaus, Florian Nagl, Andrea Christians, Wolfgang A. Schulz, Alexander Marx, Alfred C. Feller, Rainer B. Zotz, Nana Ueffing, Christoph Thorns, Christian Schwerk, Joachim Brade, Falko Fend |
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| Rok vydání: | 2009 |
| Předmět: |
Gene isoform
Protein isoform Immunology Population CASP8 and FADD-Like Apoptosis Regulating Protein Single-nucleotide polymorphism Biology Polymorphism Single Nucleotide Biochemistry Cell Line Evolution Molecular Retinoblastoma-like protein 1 HSPA2 Humans Protein Isoforms Genetic Predisposition to Disease education Lymphoma Follicular Gene HSPA9 education.field_of_study Cell Biology Hematology Molecular biology Kinetics Case-Control Studies Protein Biosynthesis RNA Splice Sites |
| Zdroj: | Blood. 114:572-579 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2009-02-204230 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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