| Popis: |
A novel family of signaling regulators, Tribbles, have recently been identified and characterized. Tribbles possess a single kinase like-domain that lacks enzyme activity and shows several severe variations from the classical kinase domain, thus it is likely to be non-functional. Interestingly, despite the lack of classical protein-protein interaction domains, which are characteristic in many signaling mediators, Tribbles are involved in multiple cellular processes such as apoptosis, tumourgenesis, cell cycle regulation and cell proliferation as well as in the development of diseases, such as diabetes and autoimmune disease through interacting with various protein kinases and transcription factors. These biological actions ofTribbles appear to be cell-type dependent. In this study, I demonstrated that expression of all three human tribbles genes is dynamically regulated by an inflammatory stimulus, IL-Ipand the pattern of regulation appears to be cell type speeific. Furthermore, not only expression pattern but also the biological action ofTribbles appears to be ce,u-type dependent. VSMC proliferation and neo-intima formation are important events in the progressIOn of atherosclerosis. These cellular processes are initiated by inflammatory cytokines and are mediated via the coordinated action of various second messenger pathways including the MAPK pathway. Our research group is interested in uncovering regulatory mechanisms of inflammation which contribute to the chronic disease of the vessel wall. In this thesis, I investigated the role ofTrb-l, which has been reported as a regulator ofMAPK pathways, in VSMC proliferation and migration. Trb-l expression levels negatively regulate VSMC proliferation and chemotaxis via the JNK pathway. The action ofTrb-1 that inhibits JNK activation and cytoplasmic interaction between JNK and MKK4 occurs by physical binding with MKK4 but not with JNK in the nucleus. This suggests an important regulatory role for Trb-l in VSMC function and a plausible mechanism that Trb-l may act as a nuclear anchor ofMK.K4. |
