Our lab is interested in molecular mechanisms of cancer biology, particularly concerning members of the Ras superfamily of proteins. Whereas normal signal transduction by Ras family proteins is required for proper cell growth and differentiation resulting from a wide variety of different inputs, their malfunction or deregulated activity is linked to uncontrolled cell proliferation or inappropriate cell suicide. Indeed, mutated Ras genes are the most commonly mutated oncogenes in human cancer, and their deregulated function as a consequence of alterations in other proteins is also a critical mechanism driving many cancer cells. In our lab, studying the mechanisms whereby Ras family proteins and their cousins control the conversion of extracellular signals to intracellular responses provides us with several broad areas of experimentation with both basic science and translational bents.

Ras proteins must be attached to the cell membrane in order to function, and this attachment requires Ras modification by an unusual lipid called a farnesyl isoprenoid. Although the basis for this requirement in Ras family signaling and transformation is not yet completely understood, a recent exciting development is that the enzyme responsible for the attachment of this lipid, farnesyl transferase (FTase), has become a target for a novel class of potential anticancer chemotherapeutic agents called FTase inhibitors, or FTIs. These compounds have potent antitumor activity in vitro and in animal model systems are surprisingly nontoxic. However, their mechanism of action has turned out to be unexpectedly complex, and we are now attempting to determine the identifies of additional non-Ras targets of FTI action as well as the bases for their tumor inhibitory properties.

Ras proteins are the prototypes for a large superfamily of related proteins with diverse functions in cellular physiology, including growth, invasion, motility, cell cycle control, differentiation, and death. One highly related protein, R-Ras, clearly differs from Ras in various functional aspects of transformation and cell death, but the genetic basis for these differences are not yet understood, and R-Ras biology is presently a relative enigma. This protein is tumorigenic in animal models, but normally uses few, if any, of the signaling pathways taken by Ras. In addition, R-Ras stimulates apoptosis, or programmed cell death, under conditions where its cousin Ras is protective. Finally, R-Ras and Ras appear to have opposing effects on the activation of integrins, which transmit signals from extracellular matrix to intracellular signaling cascades. Our lab is currently studying the molecular basis for these divergent activities between R-Ras and Ras.

Finally, long-term goals include trying to understand and then to alter the role of Ras family proteins in cellular responses to ionizing radiation. Irradiated cells must choose between death, arrest, and survival. Our ultimate goal is to learn enough about the biology to be able to tip the balance one way for healthy cells and another for cancerous cells.