TY - JOUR
T1 - Alternate transcription of the Toll-like receptor signaling cascade
AU - Wells, Christine A.
AU - Chalk, Alistair M.
AU - Forrest, Alistair
AU - Taylor, Darrin F.
AU - Waddell, Nic J.
AU - Schroder, Kate
AU - Himes, S. Roy
AU - Faulkner, Geoffrey J.
AU - Dumas, Sandra
AU - Kasukawa, Takeya
AU - Kawaji, Hideya
AU - Kai, Chikatoshi
AU - Kawai, Jun
AU - Katayama, Shintaro
AU - Carninci, Piero
AU - Hayashizaki, Yoshihide
AU - Hume, David A.
AU - Grimmond, Sean M.
PY - 2006/2/17
Y1 - 2006/2/17
N2 - Background: 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. Results: A total of 256 variant transcripts were identified, including novel variants of Tlr4, Ticam1, Tollip, Rac 1, Irak 1, 2 and 4, Mapk14/p38, Atf2 and Stat 1. 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 Mapk 14/p38 protein expression on macrophage survival were demonstrated. Conclusion: Members of the Toll-like receptor signal ing 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.
AB - Background: 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. Results: A total of 256 variant transcripts were identified, including novel variants of Tlr4, Ticam1, Tollip, Rac 1, Irak 1, 2 and 4, Mapk14/p38, Atf2 and Stat 1. 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 Mapk 14/p38 protein expression on macrophage survival were demonstrated. Conclusion: Members of the Toll-like receptor signal ing 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.
UR - http://www.scopus.com/inward/record.url?scp=33745023799&partnerID=8YFLogxK
U2 - 10.1186/gb-2006-7-2-r10
DO - 10.1186/gb-2006-7-2-r10
M3 - Article
C2 - 16507160
AN - SCOPUS:33745023799
SN - 1474-760X
VL - 7
JO - Genome Biology
JF - Genome Biology
IS - 2
M1 - R10
ER -