So ARF is a tumor suppressor, but what exactly does it do? What does it interact with and how does it stop cell growth?

Roussel: Those are the questions we want to answer. And that’s where I started to be involved full-time in ARF research. The discovery of the ARF gene itself is not mine—I want that to be very clear. I only got involved later to answer the question of how ARF is regulated and how it affects cell regulation. That required a lot of biology, and that’s my primary interest. My background is in the study of oncogenes. When I started my scientific career I discovered the Myc oncogene, as a student of Dominique Stehelin back in 1979. And Myc turns out to be important here. That is, we knew from Robert Weinberg’s observation, published in 1985, that in order for a cell to be transformed into a tumor cell it need two hits: one on an immortalizing gene and the other on a transforming gene. The immortalizing gene was Myc, and the transforming gene was ras. Weinberg showed at the time that ras and Myc both cooperated in transformation.

My hypothesis was that ARF deletion might mimic Myc function—as an immortalizing gene. So what we did with Frederique Zindy, a post-doc in the lab, was take cells from the knockout mice in which ARF had been deleted and look to see what genes would transform them. Could we transform them with ras alone? Was the addition of ras a transforming event leading to tumors? If it was, then that suggests the deletion of the ARF position was mimicking Myc function as an immortalizing gene, which turned out to be the case. That also suggested a relationship between Myc and ARF. And that’s where my contribution was. We showed that high proliferative signals, like those from Myc, led to ARF expression and apoptosis. In normal cells, the ARF-p53 pathway puts the brakes on in response to those high proliferative signals. But in tumor cells, the cells found a way to bypass those brakes because the cells want to continue growing. In different tumors, you select out cells that disable that tumor-suppressor pathway. So it has relevance to human cancer.

Could you go into a little more detail on that relevance?

Roussel: The ARF locus has been shown to be deleted in leukemias and in many different cancers. Obviously, because ARF is a tumor suppressor, its expression represents a mechanism to guard the cells against stresses. Those stresses could come from proliferative signals that force the cell to grow. Cells that are hyper-stimulated tend to die, or at least most do. Some eventually find a way to survive, and one way is to delete or mutate the genes that are putting the brakes on—to delete ARF, for instance. That allows the cell to be immortal, or to grow forever. So deletion of ARF is an immortalization mechanism. Once the cell is immortal, the chances that other genes will be hit by mutations also increase. We don’t know, really, what those other hits might be, and that’s what interests us. In other words, deleting or mutating ARF allows a cell to be immortalized, but other events still have to occur to get cancer, and that’s what we want to learn more about.

Does this give you a possible point of attack for cancer therapy?

Roussel: Yes. ARF and p53 are in the same pathway, and if the p53 gene in the tumor is untouched, then you could imagine resensitizing cells to therapy by just putting back ARF or something along those lines. The way to think of it is if p53 is intact in the tumor cells and ARF is deleted, you can reactivate p53 by putting ARF back and possibly precipitate cells into apoptosis. This is what you want to do. You want to kill the cancer cells. It’s all theoretical at this point, though.

Last question: how was the adjustment to Memphis, Tennessee, after growing up in Africa and going to school in Paris?