RAFT1/FRAP/mTOR is a key regulator of cell growth and division
and the mammalian target of rapamycin, an immunosuppressive and
anticancer drug. Rapamycin deprivation and nutrient deprivation
have similar effects on the activity of S6 kinase 1 (S6K1) and
4E-BP1, two downstream effectors of RAFT1, but the relationship
between nutrient- and rapamycin-sensitive pathways is unknown.
Using transcriptional profiling, we show that, in human BJAB B-lymphoma
cells and murine CTLL-2 T lymphocytes, rapamycin treatment affects
the expression of many genes involved in nutrient and protein
metabolism. The rapamycin-induced transcriptional profile is distinct
from those induced by glucose, glutamine, or leucine deprivation
but is most similar to that induced by amino acid deprivation.
In particular, rapamycin treatment and amino acid deprivation
up-regulate genes involved in nutrient catabolism and energy production
and down-regulate genes participating in lipid and nucleotide
synthesis and in protein synthesis, turnover, and folding. Surprisingly,
however, rapamycin had effects opposite from those of amino acid
starvation on the expression of a large group of genes involved
in the synthesis, transport, and use of amino acids. Supported
by measurements of nutrient use, the data suggest that RAFT1 is
an energy and nutrient sensor and that rapamycin mimics a signal
generated by the starvation of amino acids but that the signal
is unlikely to be the absence of amino acids themselves. These
observations underscore the importance of metabolism in controlling
lymphocyte proliferation and offer a novel explanation for immunosuppression
by rapamycin.