Protein prenylation: key to ras function and cancer intervention?

Ihe frequent association of mutated, oncogenic forms of cellular ras proteins with a broad spectrum of human malignancies has prompted intensive investigations into identifying their role in normal cellular physiology and into establishing the contribution of aberrant ras function to human tumorigenesis (1-4). Despite considerable knowledge of the structural and biochemical properties of ras proteins, we remain ignorant of the function of ras proteins. The recent discovery that ras transforming activity is critically dependent on modification (prenylation) by a farnesyl isoprenoid, an essential intermediate in cholesterol biosynthesis, has unveiled potentially important clues to ras function and identified novel prospects for cancer therapy (5-8). In this research capsule, we will summarize our present understanding of the role of protein prenylation in ras biological activity, and we will assess the promises and problems of pharmacological approaches to antagonizing prenylation. Finally, understanding the role of protein prenylation in ras function will provide a foundation for defining the significance of this previously obscure protein modification for the functions of a very diverse and growing number of isoprenylated proteins (9, 10).