Q&A with Michele Pagano, M.D.
The May Ellen and Gerald Jay Ritter Professor of Oncology and Pathology

Dr. Pagano’s laboratory has recently discovered a new tumor suppressor gene. Genes belonging to this group act like brakes on cell growth, so mutations in these genes block the cell’s ability to slow proliferation. Mutations in tumor suppressor genes are one of the ways that cancer arises.

Q: How many tumor suppressor genes are there?

A: So far, more than two dozen tumor suppressors have been identified, and fewer than 20 have been well characterized in human patients.  In the past, a tumor suppressor gene was defined by its ability to block tumors in animal models, in cell culture, and by its mutation in human tumors, but over time the definition has become looser.  Now, many scientists believe that tumor suppressor genes aren’t necessarily mutated in humans, because they can be inactivated by other means.  Yet, some researchers stick with the more restricted definition.

Q: What is your definition?

A: We try to stay in between.  In this paper we show that our new gene has tumor suppressor activity since its overexpression in cultured tumor cells inhibits their proliferation.  Therefore we speculate that it may be a bona fide tumor suppressor gene.

Q: You do a lot of work with F-box proteins. Why are they so interesting?

A:  We started our work with a strong focus on cell cycle control [the cycle by which a cell makes two copies of itself], which we know is regulated by these proteins.  In collaboration with another lab in Boston, we identified and classified 69 F-box proteins in 2004. We screened these proteins and found 15 that play a major role in controlling cell size, proliferation, and death. We are now working on these proteins because their structure and function aren’t known.

Q: Is it unusual to study one family of proteins?

A: Many laboratories either work on a single pathway or are extending their work to the entire genome without focusing on the biology of single genes. In our case, by studying a family of genes, we expanded our focus from the cell cycle to multiple cellular pathways controlling protein synthesis, epigenetic mechanisms, cell survival, DNA-damage checkpoints, the circadian clock, and other processes. By bridging different fields with our initial cell cycle work, we feel we can provide a more unbiased perspective.

Q: Do you think about how your work can be transferred to the bedside?

A: We think about treatment all the time.  We have collaborations with people at the Medical Center and with industry to explore F-box proteins as targets for cancer therapies.