Alternate transcription of the Toll-like receptor signaling cascade

Genome Biology - Tập 7 - Trang 1-17 - 2006
Christine A Wells1,2, Alistair M Chalk1,3, Alistair Forrest2, Darrin Taylor2, Nic Waddell2, Kate Schroder2, S Roy Himes2, Geoffrey Faulkner2, Sandra Lo1, Takeya Kasukawa4, Hideya Kawaji4, Chikatoshi Kai4, Jun Kawai4,5, Shintaro Katayama4, Piero Carninci4, Yoshihide Hayashizaki4,5, David A Hume2,6, Sean M Grimmond2
1Eskitis Institute for Cell and Molecular Therapies, School of Biological and Biomedical Sciences, Griffith University, Brisbane, Australia
2The Institute for Molecular Biosciences, The University of Queensland, Brisbane, Australia
3Karolinska Institutet, Stockholm, Sweden
4Genome Exploration Research Group (Genome Network Project Core Group), RIKEN Genomic Sciences Center, RIKEN Yokohama Institute, Yokohama, Kanagawa, Japan
5Genome Science Laboratory, Discovery Research Institute, RIKEN Wako Institute, Wako, Saitama, Japan
6The Special Research Centre for Functional and Applied Genomics, The University of Queensland, St Lucia, Australia

Tóm tắt

Alternate splicing of key signaling molecules in the Toll-like receptor (Tlr) cascade has been shown to dramatically alter the signaling capacity of inflammatory cells, but it is not known how common this mechanism is. We provide transcriptional evidence of widespread alternate splicing in the Toll-like receptor signaling pathway, derived from a systematic analysis of the FANTOM3 mouse data set. Functional annotation of variant proteins was assessed in light of inflammatory signaling in mouse primary macrophages, and the expression of each variant transcript was assessed by splicing arrays. A total of 256 variant transcripts were identified, including novel variants of Tlr4, Ticam1, Tollip, Rac1, Irak1, 2 and 4, Mapk14/p38, Atf2 and Stat1. The expression of variant transcripts was assessed using custom-designed splicing arrays. We functionally tested the expression of Tlr4 transcripts under a range of cytokine conditions via northern and quantitative real-time polymerase chain reaction. The effects of variant Mapk14/p38 protein expression on macrophage survival were demonstrated. Members of the Toll-like receptor signaling pathway are highly alternatively spliced, producing a large number of novel proteins with the potential to functionally alter inflammatory outcomes. These variants are expressed in primary mouse macrophages in response to inflammatory mediators such as interferon-γ and lipopolysaccharide. Our data suggest a surprisingly common role for variant proteins in diversification/repression of inflammatory signaling.

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Genome Biology

Tập 7

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