Giannini, Ana Lucia Moraes; (2001) The Regulation of β-catenin signalling by α-catenin. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Alpha-catenin and β-catenin link cadherins to the cytoskeleton at sites of cell-cell contact. Beta-catenin also associates with Tcf/Lef-1 transcription factors, activating transcription of genes encoding proteins involved in cell cycle regulation and differentiation, such as cyclin D1 and c-myc. Mutations in β-catenin that lead to its stabilisation and accumulation in the nucleus are associated with increased proliferation of colon cancer cells. This thesis examines the regulation of β-catenin signalling by a- catenin. It shows that overexpression of β-catenin results in formation of intranuclear rod-like structures. The rod-like structures are disrupted by co-expression of proteins that interact with the armadillo repeat domain of β-catenin. In contrast, exogenous α-catenin prevents nuclear entry of the rod-like structures. However α-catenin translocates to the nucleus in cells expressing β-catenin and Tcf/Lef-1. Endogenous α-catenin is present both in the nucleus and in the cytoplasm of colon cancer cells. A variant cell line that lacks α-catenin shows a significant increase in β-catenin/Tcf-dependent transcription, compared to that in the α-catenin-positive parental cell line. A nuclear- targeted form of α-catenin inhibits β-catenin/Tcf activity to a similar extent as wild type α-catenin in these cells. These observations indicate that α-catenin can inhibit β-catenin/Tcf activity in the nucleus. In vitro experiments show that α-catenin inhibits the association of the β-catenin/Tcf complex with its target DNA. While nuclear import of α-catenin is mediated by the β-catenin/Tcf complex, nuclear export of a-catenin is mediated by nuclear export signals present at its amino-terminal domain. These lie within the β-catenin- binding domain, suggesting that their accessibility is regulated by binding to β-catenin. Thus the nuclear export of α-catenin may be linked to the regulation of β-catenin/Tcf activity in the nucleus.

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