Cell Biology

Edited by: Eugene Russo and Steve Bunk J. Behrens, J.P. von Kries, M. Kühl, L. Bruhn, D. Wedlich, R. Grosschedl, W. Birchmeier, "Functional interaction of ß-catenin with the transcription factor LEF-1," Nature, 382:638-42, 1996. (Cited in more than 285 papers since publication) Comments by Walter Birchmeier, professor of cell biology, Max Delbrück Center for Molecular Medicine, Berlin, Germany In the tiny world of signaling pathways that carry biochemical reactions, the pathway of the gene wnt is vital to early organismal development. The gene's name is an abbreviation of "wingless-type," which refers to the fate of a fruit fly that suffers a specific mutation in this pathway. In humans, the wnt pathway controls development of numerous organs, including the brain, the peripheral nervous system, the limbs, and the kidney. It contains various oncogenes, such as wnt and myc (the latter is short for avian myelocytomatosis, a cancer principally of the sternum and liver in fowl). But this pathway also contains genes that suppress tumors. Specifically, it controls tumor formation in the colon and in melanomas. Throughout this decade, tracing the pathway's complex biochemical signaling has occupied researchers' time.1 Picture a maze of nanodoors, before each of which a key is concealed. If the key can be found and fitted to the lock, the prize behind that door is another key for the next door, and so on. But no solitary Theseus could ever negotiate this labyrinth, and when the band of biologists who for years have shared each other's secrets finally do unlock the last door, they will be well prepared to face the wnt pathway's Minotaur, cancer. The door opened by this paper revealed how the wnt pathway communicates with nuclear DNA. The key to that door was knowing the two roles of a certain cytoplasmic protein in vertebrates called ß-catenin. It not only participates in wnt signaling but also links up cell-adhesion molecules with the cytoskeleton. Given these two roles, scientists in Germany and the United States, led by Walter Birchmeier, set out to find a connection between cell adhesion molecules and the nucleus by searching for new interaction partners with ß-catenin. They made a number of discoveries. They determined that ß-catenin binds directly with a protein that influences the cell's internal architecture by inducing a sharp bend in the DNA helix. Such bending is thought to affect gene regulation. They learned that this protein, called lymphoid enhancer-binding factor (LEF-1), transports ß-catenin to the nucleus, and that ß-catenin modulates the DNA-binding properties of LEF-1. It also decreases the bend angle of the DNA helix induced by LEF-1 by about 40 percent. The latter effect meant that ß-catenin itself could be influential in gene regulation. Moreover, they showed that LEF-1, like ß-catenin and members of the wnt pathway, induces axis duplication of frog embryos. A mutant form of LEF-1, therefore, could interfere with embryonic axis development. Since these discoveries about the links between the cell adhesion process, the wnt pathway, and gene regulation were made, it has been found that the heterodimer, or molecular compound, of ß-catenin and LEF-1 is the actual transcription factor, central to cellular development.2 "LEF-1 provides the DNA-binding domain, where [DNA helix] bending may play a role, whereas the C-terminus of ß-catenin represents the activation domain, which controls the basic transcriptional machinery," Birchmeier explains. He adds that target genes of ß-catenin and LEF-1, such as the c-myc oncogene, have also been identified. When the tumor suppressor gene called adenomatous polyposis coli (APC) is inactivated, as in most colorectal cancers, mutations of it cause aberrant accumulation of ß-catenin, which then binds to T-cell factor (TCF), a relative of LEF-1, causing increased transcriptional activation of target genes, including c-myc.3 "Our own lab has recently continued to work on the role of the new protein conductin," Birchmeier reports, "which ... controls the stability of ß-catenin."4 As more doors open and scientific knowledge increases, the Minotaur's power continues to diminish. A.P. McMahon and A. Bradley, "The Wnt-1 (int-1) proto-oncogene is required for development of a large region of the mouse brain," Cell, 62:1073-85, 1990. H. Clevers and M. van de Wetering, "TCF/LEF factor earn their wings," Trends in Genetics, 13:485-9, 1997. T.C. He et al., "Identification of c-MYC as a target of the APC pathway," Science, 281:1509-12, Sept. 4, 1998. J. Behrens et al., "Functional interaction of an axin homolog, conductin, with ß-catenin, APC and GSK3ß," Science, 280:596-9, April 24, 1998.

Cell Biology

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