Cancer and the yeast.

Malignancy arises from an abnormally in a select group of normal cellular genes in their control, according to a major hypothesis among cancer researchers today. An important question is, what role do these genes normally play in a cell? James Broach of Princeton University, Michael Wigler of the Cold Spring Harbor (N.Y.) Laboratory and colleagues have now answered this question for one of the genes -- at least as it performs in yeast cells. The answer: The gene called ras modulates the activity of a regulatory enzyme called adenylate cyclase.

The yeast Saccharomyces cerebisiae has two genes that are similar to the human gene, c-ras, which has been implicated in bladder cancer. The yeast genes, RAS1 and RAS2, appear to be involved in a yeast cell's decision about whether to reproduce by cell division or to form spores. A normal yeast chooses cell division when nutrients are plentiful, and sporulation when nutrients are scarce. But a yeast with reduced RAS activity sporulates even in the presence of excess nutrients, and yeast with no active RAS gene cannot survive. In experiments with genetically engineered yeast, however, a transplanted human c-ras gene can substitute for the yeast gene and the cell will grow normally. "The human gene can work in the yeast system," Broach says.

The ras gene associated with human cancer is a mutant that produces a protein with one altered amino acid (SN: 11/13/82, p. 316). The scientists have examined a yeast RAS gene with the corresponding mutation. They find that yeast cells carrying this mutant gene (called RAS-vall9) also are impaired in the divide-or-sporulate decision. The mutant always enters into cell division even if there are insufficient nutrients. This overenthusiasm for cell division might be considered the yeast equivalent of malignancy.

The scientists soon realized that the RAS mutant were similar to another set or yeast strains. Yeast lacking adenylate cyclase -- the enzyme that makes cyclic AMP, a small regulatory molecule--cannot begin cell division. On the other hand, strains that bypass the need for adenylate cyclase always begin cell division, even under inappropriate conditions. By putting different combinations of the genes into yeast, the researchers determined that the RAS gene products regulate growth in yeast solely by modulating adenylate cyclase activity. Biochemical measurements backed up this conclusion. "We haven't sorted it all out yet," Broach says, "but the analogies between the yeast and human situations are striking."