Williams, Timothy Mark;
(2000)
Signal transduction through JAK1: The effect of a mutant on the induction of class II HLA by interferon-gamma, antiviral responses, and the response to dsRNA.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
The protein tyrosine kinase JAK1 is integral to signal transduction in response to the Interferons (IFNs), many cytokines and a number of growth factors. A recombinant mutant of JAKl (JAK1ΔB) with an interesting dominant-negative phenotype has been characterised. Stable expression in human cells of the mutant JAK1 has no effect on the activation of the JAK/STAT pathway by IFNγ but results in selective inhibition of the induction of Class II HLA and the antiviral response. There is little effect on the response to α/β IFNs. Consistent with the inhibition of the Class II response, IFNγ induction of the transcription factor CIITA (which is essential for expression of Class II) is inhibited, as is expression from reporter constructs driven by the IFNγ-inducible promoter of CIITA. There is no detectable effect on factors known to interact with the promoter, suggesting a possible inhibition by JAK1ΔB of a novel JAK1-dependent signal(s) regulating the assembly or function of higher order transcription complexes. Despite the relative selectivity of the effects on CIITA and Class II HLA, expression profiling using DNA oligonucleotide arrays indicated that as many as 10% of the IFNγ induced genes may be affected by the mutant JAK1. JAK1ΔB inhibits the induction of genes in response to dsRNA, reflecting an inhibition of both NFKB activation and IRF3 function. Although IFNγ primes the induction of IFNβ and, for example, the activation of p38 MAP kinase in response to dsRNA, the results of a more detailed analysis argue against a major role for IFNγ priming of dsRNA induction of Type I IFNs or IFN inducible genes in the primary antiviral response.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Signal transduction through JAK1: The effect of a mutant on the induction of class II HLA by interferon-gamma, antiviral responses, and the response to dsRNA |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Thesis digitised by ProQuest. |
| Keywords: | Biological sciences; Signal transduction |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10102739 |
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