Cancer Biology, Molecular Biology
University of Colorado at Boulder
Dr. Espinosa is also an assistant professor in the Department of Molecular, Cellular, and Developmental Biology at the University of Colorado at Boulder.
Joaquín Espinosa investigates the p53 tumor-suppressor gene network, with the goal of designing novel therapeutic strategies for selective elimination of cancer cells.
Some genes play a central role in controlling a particular cellular function or behavior, but they don’t act alone. Finding out why has become a key theme in the work of Joaquín Espinosa, who is studying one of the most prominent genes in cancer biology: the p53 tumor suppressor gene.
“Genes are not soloists,” he’s fond of saying. “We need to decipher the configurations of p53’s surrounding network to understand how p53 works. The network is likely to be composed of hundreds, if not thousands, of genes that have meaningful interactions with p53.”
The p53 gene encodes a protein, which in its normal form, protects cells against cancer. The p53 protein is called the “guardian of the genome” because it triggers the suicide of cells with damaged DNA. Inactivation of p53 can set the stage for the development of different types of cancer.
Over the years, researchers have uncovered several of p53’s anticancer activities. For example, when p53 recognizes DNA damage in cells, it activates proteins that repair DNA. It also arrests the cell-division cycle to give DNA repair proteins time to go to work, and then allows the cell cycle to resume. In some situations, p53 doesn’t tell damaged cells to stop dividing, but rather instructs them to kill themselves—a phenomenon known as programmed cell death or apoptosis.
Espinosa, a molecular biologist at the University of Colorado at Boulder, has made important contributions to understanding how p53 regulates the expression of other proteins to stop tumor growth. But many questions remain. Over the past three decades, researchers have published more than 45,000 articles about p53, but they continue to be stymied about many of p53’s behaviors. For Espinosa, a central question looms large: How do cells know what to do when p53 is activated?
The answer, Espinosa believes, may come from defining the complex network of activities and interactions in which p53 participates. One of his ambitious plans is to catalog all of p53’s activities and show how these activities change in different cell types and under different conditions. In the process, he hopes to expose new targets for the next generation of anticancer drugs.
He plans to inactivate all the genes in a cell, one by one, and then test the cell’s behavior—a technique referred to as a genetic screen—to identify genes that play a role in either enabling or obstructing p53’s functions. “With genetic screening we have the ability to, in effect, ask every gene in the genome how it relates to p53,” he says. “We can inactivate each gene and test what cells want to do in the absence of that gene: die, survive by arresting their cycle, or simply show indifference.”
Espinosa would also like to combine these genetic approaches with proteomic technologies to ask the same questions of proteins—for example, are particular modifications on a protein associated with a certain cellular behavior?
Once the p53 network is better defined, Espinosa will be able to probe how altering it influences cancer development and response to treatment in animal models and human tissues. The network approach, Espinosa believes, will “move the understanding of p53 and gene networks in general to an entirely new level.”
Espinosa is a native of Argentina and the first in his family to attend college. His technical papers and writings are often teeming with analogies—he likes to refer to p53 as the CEO of a large company (the cell). By itself, it doesn’t do much, but it makes important decisions based on input from many different sources, proteins and other cofactors, and it delegates tasks. “The CEO is one of the most heavily connected persons within a company,” says Espinosa. “It’s the same with p53 and the cell. You don’t understand how it works alone. You have to know its companions.”