by Dr. Jason Lieb
Volume 2/Number 3
|  | | Dr. Lieb, wife Mary and daughter Anna. | My laboratory was established last year at the University of North Carolina in Chapel Hill. We aim to understand a very basic unsolved problem in biology that is relevant to cancer: How do proteins that interact with DNA find their proper targets in living cells? We study this problem in yeast, a single-celled fungus, and C. elegans, a very simple roundworm that lives in the soil (C. elegans is not the kind of worm you may have in mind: it is transparent, about the size of a piece of lint, and is barely visible with the naked eye). Why do we use these strange creatures to study this problem, and what does it have to do with understanding cancer?
The research community’s understanding of how cancer arises and how to treat it has come from some unexpected sources. For example, all cells (plant, animal, and fungi) control their rate of growth through a very carefully regulated process called the “cell cycle”. In humans, when the regulation of the cell cycle is disrupted, cells may begin to divide uncontrollably and cause cancer. Understanding the cell cycle is critical to our understanding of the origins and treatment of cancer. However, most of what we know about how the cell cycle works was not discovered initially using human cells, but in yeast cells. Yes, Saccharomyces cerevisiae, the very same yeast that is used to brew beer and make bread. It turns out that the molecular components used to regulate the cell cycle in yeast and humans are remarkably similar to each other. This is not only true for the cell cycle, but for many other basic processes that are required for the growth and maintenance of cells. Therefore, researchers often use simpler organisms, like yeast, to figure out the details of processes that are fundamental to all living things. Then these discoveries are tested in more complicated systems, where the knowledge can be used as the basis for creating drugs or other therapies to cure disease. The advantage is that yeast cells grow very quickly and are easy to manipulate in the lab, allowing discoveries to be made much more rapidly than they would be if human cells were studied first.
We use yeast and worms to study how DNA-binding proteins called transcription factors find their proper targets in living cells. Transcription factors control which genes get turned on and off, when those genes get turned on and off, and in what tissues they get turned on and off. Using a new research tool called the DNA microarray, we are able to map all of the sites of interaction between any given transcription factor and the entire yeast genome (a “genome” is simply all of the DNA that makes up the chromosomes that are in a cell). We have begun to uncover some of the rules that proteins use to find their targets in yeast. For example, we were able to provide conclusive genome-wide evidence that DNA sequence information alone is not sufficient to direct a binding event.  | | Dr. Lieb's pride and joy -- daughtersKarina and Anna. | Even though many regions of the genome may contain a DNA sequence a transcription factor likes to bind, only sequences that are in particular parts of the genome are actually bound. The V foundation has provided funding to test whether the rules that proteins use in yeast also are used in a much more complicated system, C. elegans (these are the worms). Worms are simple compared to humans, but are much more complicated than a yeast cell. For example, worms have muscle, a nervous system, and a gut, all things yeast don’t have. Therefore, worms are an important stepping stone in determining whether the way transcription factors behave in yeast is similar to the way they behave in humans. Why is understanding how transcription factors find their targets is important to understanding cancer?
Cancers occur when mutations in DNA lead to improper regulation of genes that control cell growth. It is likely that in all cancers, alterations in the abundance or binding specificity of at least one transcription factor contributes directly to uncontrolled cell proliferation. As one example, Burkitt’s lymphoma is caused when a transcription factor called c-myc is turned on in improperly in immune cells, which in turn leads to inappropriate gene regulation and cancer. Another example is a protein called CTCF, which is involved in the occurrence of breast, prostate, and kidney tumors. When CTCF is mutated, the DNA binding spectrum of CTCF changes such that it no longer bind to its proper targets involved in regulating cell proliferation, but instead binds other targets. In both examples, which serve as general illustrations for numerous other cancers, alterations in the natural range of a transcription factor’s gene targets are likely major factors in the development of cancer. We anticipate that our studies of DNA-binding specificity will lead to better predictions of the targets of human transcription factors that have the potential to cause cancer, which may ultimately lead to new therapies based on inhibiting binding to inappropriate targets. Successful completion of our proposal will also lay the groundwork for experiments in mammalian systems to examine how any cancerous state affects the distribution of DNA-binding proteins, and how that altered distribution contributes to progression towards malignancy.
Over the years it has become increasingly clear that basic research is essential to our common long-term goal of eliminating cancer. The importance of this goal was reinforced by news I received while writing this essay. Ira Herskowitz, a brilliant and influential yeast researcher who had been fighting pancreatic cancer, had died. Like so many people stricken with cancer, just a short time ago it seemed he had many years of productive work and life ahead of him. We have all been touched by cancer, and hope for the day that all cancers can be effectively managed or prevented. The V Foundation recognizes the value in funding a combination of basic and clinical research, to balance immediate advances in cancer therapy and prevention with our long-term goal of understanding and conquering this disease. I deeply appreciate their support. | ..............................................................................................................................
Editor's Note: |  | Dr. Lieb | Dr. Lieb enjoys playing basketball and tennis, and he tries to play one or the other at least once a week to stay in shape.
While he's working at home in the evening, he likes to listen to baseball on the radio during the summer. He's currently enjoying the start of the Durham Bulls season, but really the team does not even matter," I just enjoy the relaxing cadence of the sport and the broadcasts." The Lieb family also attends several games a year.
Before the arrival of the little Liebs, Jason, and wife Mary enjoyed going out to hear live jazz and bluegrass; now he spends most of his free time at the playground or swimming pool with Karina and Anna. |
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