Armadillo, Pangolin, Fruit Flies and Tumor Cells

A fruit fly protein called armadillo may soon be helping scientists understand the mechanisms associated with perhaps 90 percent of all cases of colon cancer and some cases of the skin cancer melanoma. Armadillo and another important protein called pangolin were found by researchers studying the cell signaling pathways involved in the development of fruit fly embryos. The scientists named their proteins for mammals that have bony plates because flies with mutations in these genes grow lots of spiky little hairs.

Excitement about the fruit fly work heightened considerably when the scientists--NIGMS grantee Mark Peifer, Ph.D., at the University of North Carolina at Chapel Hill and colleagues--realized that armadillo is essentially the same as the human protein beta-catenin. Defects in beta-catenin or its regulation appear to underlie a vast majority of all cases of colon cancer and some cases of melanoma, as well. Clearly, the researchers knew, understanding how armadillo works could be very important for human health and the years of painstaking study of the fruit fly signaling pathways made such understanding possible.

At first, however, Dr. Peifer and his colleagues were puzzled. Although they found the armadillo protein in the nucleus, they could find no evidence that it bound to the DNA molecule. Such binding is critical to turning on gene transcription, which, in turn, may cause cancer cells to proliferate. Eventually, Dr. Peifer's group was able to show that armadillo binds to pangolin in the nucleus and that it is the complex of the two proteins that binds DNA and initiates transcription. Other scientists have shown that a virtually identical process occurs in human colon cancer, where beta-catenin binds a protein called Lef that is homologous to pangolin, and the resulting complex turns on gene activity.

Now that researchers understand some of the basic biochemistry of the molecules involved, they will study the process further in fruit flies, where results are easier and faster to obtain than in humans or even mice. For instance, the scientists may be able to look for small molecules that interfere with armadillo and pangolin binding and turn off or block the signaling pathway that leads to tumor formation. If found, these molecules would be candidates for future drugs to treat colon cancer.

REFERENCE

van de Wetering M, Cavallo R, Dooijes D, van Beest M, van Es J, Loureiro J, Ypma A, Hursh D, Jones T, Bejsovec A, Peifer M, Mortin M, Clevers H. Armadillo Co-Activates Transcription Driven by the Product of the Drosophila Segment Polarity Gene dTCF. Cell 1997;88:789-99.

OTHER REFERENCES

Brunner E, Peter O, Schweizer L, Basler K. Pangolin Encodes a Lef-1 homolog that Acts Downstream of Armadillo to Transduce the Wingless Signal. Nature 1997;385:829-33.

Riese J, Yu X, Munnerlyn A, Eresh S, Hsu S-C, Grosschedl R, Bienz M. LEF-1, a Nuclear Factor Coordinating Signalling Inputs from Wingless and Decapentaplegic. Cell 1997;88:777-87.

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