Cytokine regulation of beta-catenin signaling

The canonical Wnt signaling pathway, so named after its ligands, is involved in many differentiation events, such as proliferation and motility, especially during embryonic development. When aberrantly activated, Wnt signaling leads to tumor formation, however, Wnt protein themselves are rarely involved in the activation of the pathway during carcinogenesis. More often, mutations involving downstream components such as APC or beta-catenin result in nuclear accumulation of beta-catenin, which subsequently complexes with T-cell factor/lymphoid enhancing factor (TCF/LEF) transcription factors to cause gene transcription and results in cellular proliferation and ultimately, cancer. Mutations in APC or beta-catenin occur in virtually all colorectal cancers. It is the focus of this study to examine new ways in which this pathway is regulated.; This project has discovered that the cytokine, tumor necrosis factor-alpha and ectodysplasin (Eda) and the ectodysplasin receptor (Edar), regulate beta-catenin signaling activity. A conserved consensus sequence, DSGXXS, within the N-terminus of beta catenin and IkappaB, allows for targeted phosphorylation by upstream kinases, such as IkappaB kinase. Evidence show that tumor necrosis factor-alpha is able to regulate betacatenin through the IkappaB kinase (IKK) complex. The IKK complex is normally involved in inactivating the inhibitor, IkappaB which normally sequesters nuclear factorkappaB in the cytoplasm. Inactivation of IkappaB involves targeted phosphorylation at two serine residues and its degradation via the 26S proteosome. Inactivation of IkappaB releases nuclear factor-kappaB, allowing it to translocate into the nucleus and activate target genes. Lesions in the ectodysplasin gene cause a condition known as hypohidrotic (anhidrotic) ectodermal dysplasia, characterized morphologically by rudimentary teeth, sparse hair, and absence of sweat glands. Indirect evidence suggests that the ectodysplasin gene may interact with the Wnt pathway during hair follicle initiation. Beta-catenin induces de novo morphogenesis of hair follicles and it has also been implicated in the regulation of epidermal development.; In the second part of this project, this study provides evidence that nuclear factorkappaB signaling is independent of IKK regulation of beta-catenin. The following results also show that Wnt signaling is not the only way beta-catenin is regulated. This study shows that cytokine induced decrease in beta-catenin signaling activity, is not due to beta-catenin degradation but rather, to its re-distribution. Furthermore, it is likely that an 'active' fraction of beta-catenin present within the nucleus that is responsible for its signaling activity, and that both tumor necrosis factor-alpha and ectodysplasin reduce or redistribute that fraction. This study discovers that beta-catenin may be regulated by activated IKK and cytokine, tumor necrosis factor-alpha as well as ectodysplasin and its receptor, Edar. This study also confirm that there is a small pool of beta-catenin present within the nucleus, that is transcriptionally active and this is reduced significantly after treatment with tumor necrosis factor-alpha or over-expression of Edar. Thus this project has provided great insight of the ways into which beta-catenin may be regulated within the cell and the complexity of its regulation in different signaling pathways.