Maria Cardenas-Corona, PhD
Research Professor

We are studying the Tor signaling cascade, which senses nutrients and regulates gene expression, translation, and ribosome biogenesis and has been conserved over a billion years of evolution from yeast to humans. The Tor proteins are novel protein kinases whose functions are inhibited by the immunosuppressive antifungal drug rapamycin in complex with the prolyl isomerase FKBP12. We focus on the antiproliferative drug rapamycin, which suppresses the immune system by blocking signaling events required for activation of T-lymphocytes. Rapamycin is used to treat and prevent graft rejection in organ transplant recipients. Rapamycin is a product of a soil bacterium and likely plays a role in nature distinct from immunosuppression, possibly as a toxin to inhibit growth of competing microorganisms. Based on this hypothesis, we have analyzed in detail the mechanisms of rapamycin action in the yeast Saccharomyces cerevisiae.

Saccharomyces cerevisiae is an outstanding model system, the complete genomic sequence has been determined and annotated, whole genome DNA arrays are available for gene expression studies, and a complete set of gene disruption strains is being constructed by an international consortium. These advances promise to revolutionize our understanding of cellular function. Over the past several years, we have conducted a structure-function analysis of the yeast and mammalian Tor kinases that revealed a novel toxic domain that likely interacts with effectors or regulators of this signaling cascade and showed that the Tor kinase domain is functionally conserved between yeast and humans. Using whole genome arrays, we discovered a novel role for the Tor signaling cascade in regulating gene expression in response to nutrients. Recently we have also found that the Tor pathway regulates filamentous differentiation of yeast cells in response to nutrient limitation. Our findings define a nutrient sensing signaling cascade conserved from yeast to humans. Rapamycin was approved by the FDA in August 1999 as an immuosuppressive agent to prevent and treat graft rejection in organ transplant recipients. Phase I/II clinical trials are now in progress with rapamycin as a novel chemotherapy agent in several different types of solid organ tumors. Thus, the potential for significant advances in both basic and clinical science are outstanding.