Our lab studies signal transduction via an evolutionarily conserved
kinase called mTOR, the mammalian target of rapamycin (also known
as FRAP). mTOR integrates signals from growth factors, nutrients,
and energy to regulate fundamental cellular processes such as cell
growth (an increase
in cell mass and size through macromolecular biosynthesis) and cell
cycle progression. Coordination of cell growth and cell cycle progression
by mTOR is important not only for cells to maintain a characteristic
size as they undergo sequential cell divisions during a proliferative
response but ensures that organs and indeed whole organisms develop
normally to a characteristic size. While mTOR is best known to regulate
the initiation of protein synthesis via the ribosomal protein S6
kinase (S6K) and eukaryotic initiation factor 4E (eIF4E) binding
protein (4EBP) pathways, it is becoming clear that mTOR has many
functions in diverse cellular processes, including transcription
and protein stability.
The naturally occurring drug rapamycin specifically inhibits mTOR-dependent
signaling and causes cells to proliferate slowly at a reduced cell
size, consistent with the role of mTOR in controlling protein biosynthesis
and cell growth. The medical relevance of understanding mTOR biology
is underscored by the fact that rapamycin is an FDA approved immunosuppressive
drug for inhibiting kidney transplant rejection (due to its potent
inhibition of immune cell proliferation) and a cardiology drug
to inhibit the restenosis that often occurs after angioplasty.
mTOR is also emerging as a novel target for cancer therapeutics-
Due to the ability of rapamycin to inhibit cell proliferation,
rapamycin analogs are currently being tested in clinical trials
for efficacy against a variety of human tumors.
While significant progress has been made in understanding mTOR
function, many important questions remain: How is mTOR regulated
by upstream signals, such as those derived from nutrients, growth
factors, and energy? Precisely how does rapamycin inhibit mTOR-dependent
signaling? How does mTOR and downstream signaling pathways, such
as the S6K and 4EBP pathways, drive cell growth and cell cycle
progression, and importantly, how does mTOR coordinate these fundamental
processes? By manipulating mTOR expression using the mouse as a
model, we hope to better understand the in vivo function of mTOR
and its contribution to animal physiology. Using cell culture and
the mouse as model systems and employing a variety of techniques
in molecular biology, cell biology, and biochemistry, we are working
toward better understanding mTOR function, a signaling molecule
with significant medical relevance.
- Fingar DC and Blenis J. (2004) The Target of Rapamycin (TOR):
An integrator of nutrient and growth factor signals and coordinator
of cell growth and cell cycle progression.
Oncogene 23 (18):
3151-3171
- Fingar DC, Tee AR, Richardson CJ, Cheatham L, Tsou C, and
Blenis, J. (2004) mTOR-dependent cell cycle progression is controlled
by
its downstream targets and cell growth effectors S6K1 and 4EBP1/eIF4E.
Mol. Cell. Biol. 24(1): 200-216.
- Schalm S, Fingar DC, and Blenis, J. (2003) TOS-motif-mediated
raptor binding is required for 4EBP1 phosphorylation and function.
Current Biology. 13: 797-806.
- Tee AR, Fingar DC, Manning BD, Kwiatkowski DJ, Cantley LC,
and Blenis, J. (2002) Tuberous sclerosis complex-1 and –2
gene products function together to inhibit phosphoinositide-3-kinase-dependent
signaling through mammalian target of rapamycin. PNAS 99(21):
13571-13576.
- Fingar DC, Salama, S Tsou, C, Harlow E and Blenis, J. (2002)
Mammalian cell size is controlled by mTOR and its downstream
targets S6K1 and 4EBP1/eIF4E. Genes and Dev. 16: 1472-1487.
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