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.
