The intricate interplay of cellular signaling pathways provides a beehive of biologic activity in the nucleus. Understanding how these pathways function and dysfunction not only helps trace the roots of cancers and genetic disorders but also suggests new therapeutic targets. At the recently held Gordon Conference on “Signal Transduction within the Nucleus,” GEN spoke with several presenters who shared their insights into this cutting-edge field.
“Behold the awesome power of yeast genetics and biochemistry,” proclaimed Ali Shilatifard, Ph.D., investigator with the Stowers Institute, as he began his keynote address. Dr. Shilatifard, who also was a co-organizer of the conference, described lessons learned from yeast about human leukemia. “My research focuses on work related to lymphocytic leukemia and mixed-lineage leukemia (MLL).
“This childhood cancer results from translocations in the MLL gene on chromosome 11. For unknown reasons, the gene appears to break in infancy. Its translocation causes leukemia with a very poor prognosis. This gene was discovered over 25 years ago by clinicians, however for a long time we did not understand its function. Therefore, we decided to take the road less traveled and use yeast as a model system to investigate the molecular functions of the MLL homologue.”
According to Dr. Shilatifard, Saccharomyces cerevisiae expresses an MLL homologue called Set1. “Yeast has been a great model system to begin dissecting our way through this pathway. We found that Set1 is a component of a larger complex we named COMPASS (complex proteins associated with Set1). Human MLL is also found in a COMPASS-like complex. Further, we determined that COMPASS can modify histone methylation, and based on these findings it was demonstrated that the MLL complex is also a histone methylase. This gives us clues as to how to find possible therapeutic targets. For example, inhibiting or modulating methylation/demethylation could be the basis for targeted treatments.”
Lately, model systems have been ignored and sidelined by funding agencies in favor of translational studies, noted Dr. Shilatifard. “I think some people do not understand the absolute power of a model system. Sarah Palin, for example, asked why should we study fruit flies. However, Drosophila, yeast, zebrafish, and other simple model systems all have the capacity to provide us with much-needed information.”