Use this URL to cite or link to this record in EThOS:
Title: The role of mitogen activated protein kinases in interleukin-1 signalling
Author: Finch, A.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 1999
Availability of Full Text:
Full text unavailable from EThOS.
Please contact the current institution’s library for further details.
Interleukin-1 (IL-1) is a potent pro-inflammatory cytokine produced mainly by monocytes and macrophages in response to bacterial infection and other harmful stimuli. The binding of IL-1 to its type 1 receptor leads to activation of several intracellular signalling molecules, including the three major Mitogen Activated Protein kinases (MAPKs): p42 MAPK, p38 MAPK and p54 MAPK, which is also known as Jun N-terminal kinase (JNK) or Stress Activated Protein kinase (SAPK). Strong activation of JNK/SAPK was observed in rabbit liver upon systemic administration of IL-1. This tissue was therefore used as a source to look for an IL-1-regulated activator of this protein kinase. A single activator was identified and, although it could not be purified by sequential column chromatography, it was identified using an antiserum of MAPK kinase 7 (MKK7), a newly identified activator of JNK/SAPK. It was not recognised by an antiserum to MKK4, the only other known activator of this MAPK. Activation of p38 MAPK in rabbit liver was not regulated by IL-1. Instead, a constitutively active p38 MAPK kinase was identified. Mutants of recombinant p38 MAPK were constructed to show that the activator phosphorylated the threonine and tyrosine residues of p38 MAPK, revealing it to be a dual-specificity kinase, like the other known MKKs. An antiserum which recognised MKK3 and MKK6 strongly precipitated the activator. Assays were developed so that the three MAPKs could be immunoprecipitated from various tissues and their activities measured. In most cell lines, IL-1 activates JNK/SAPK and p38 MAPK and in some it activates p42 MAPK. In five tissues JNK/SAPK was strongly regulated by IL-1 whilst p38 and p42 MAPKs were not. Antisera which recognise distinct JNK/SAPKs were also tested and revealed that the 54 and 46 kDa forms of JNK2/SAPKα were the main JNK/SAPK forms activated in the tissues.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available