01 Apr 1999

β-catenin, a protein that regulates transcription, has drawn attention in Alzheimer's research because it interacts with PS1 and PS2. It was also recently found that AD patients with the PS1 mutation have markedly reduced β-catenin in their brains. The two articles described below address the gene targets of β-catenin and the regulation of β-catenin itself (in the context of colon cancer) and add detail to the portrait of this protein.

In probing the causes of oncogenesis in colon carcinoma and other cancers, researchers have been led to a constellation of signaling molecules, including β-catenin, GSK3-β, and axin, whose interactions revolve around the adenomatous polyposis coli (APC) protein. APC appears to act as a scaffold for the assembly of these molecules. Disruptions in this system, for example the mutations in APC found in most human colon cancers, are thought to lead to abnormal cellular accumulation of β-catenin, which in turn binds to the TCF/LEF family of transcription factors and activates transcription of target genes.

Tetsu and McCormick, reporting in today's Nature, have identified the protein cyclin D1, a factor in cell division that is overexpressed in many colon carcinomas, as one of those target genes. They show that β-catenin activates transcription from the cyclin D1 promoter region and that this activation requires the presence of regions of the promoter that are bound by TCF/LEF proteins. They also show that mutant β-catenin leads to abnormally high levels of cyclin D1 in the HeLa cell culture line and describe interactions between β-catenin and Ras mutations that increase cyclin D1 transcription.

In studying the APC protein and its activity, Seeling and colleagues have found an additional factor-protein phosphatase 2A (PP2A)-that interacts with APC. Reporting in Science, they show that PP2A, via its B56 subunit, can regulate β-catenin levels in living cells. Expression of B56 reduced cellular levels of β-catenin and inhibited transcription of β-catenin target genes. The researchers found that a mutation of APC blocked this reduction, indicating that the B56-mediated action is dependent on an intact APC protein. They also found that a mutation of β-catenin blocked the B56-mediated reduction. The location of that particular mutation, and the fact that proteasome inhibitors also blocked the action of B56, suggest that B56 exerts its affects through a process that ends with phosphorylation-induced proteasomal degradation of β-catenin.—Hakon Heimer