PMID- 12271141
OWN - NLM
STAT- MEDLINE
DCOM- 20021204
LR  - 20211203
IS  - 0027-8424 (Print)
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Linking)
VI  - 99
IP  - 21
DP  - 2002 Oct 15
TI  - Tuberous sclerosis complex-1 and -2 gene products function together to inhibit 
      mammalian target of rapamycin (mTOR)-mediated downstream signaling.
PG  - 13571-6
AB  - Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder that 
      occurs upon mutation of either the TSC1 or TSC2 genes, which encode the protein 
      products hamartin and tuberin, respectively. Here, we show that hamartin and 
      tuberin function together to inhibit mammalian target of rapamycin 
      (mTOR)-mediated signaling to eukaryotic initiation factor 4E-binding protein 1 
      (4E-BP1) and ribosomal protein S6 kinase 1 (S6K1). First, coexpression of 
      hamartin and tuberin repressed phosphorylation of 4E-BP1, resulting in increased 
      association of 4E-BP1 with eIF4E; importantly, a mutant of TSC2 derived from TSC 
      patients was defective in repressing phosphorylation of 4E-BP1. Second, the 
      activity of S6K1 was repressed by coexpression of hamartin and tuberin, but the 
      activity of rapamycin-resistant mutants of S6K1 were not affected, implicating 
      mTOR in the TSC-mediated inhibitory effect on S6K1. Third, hamartin and tuberin 
      blocked the ability of amino acids to activate S6K1 within nutrient-deprived 
      cells, a process that is dependent on mTOR. These findings strongly implicate the 
      tuberin-hamartin tumor suppressor complex as an inhibitor of mTOR and suggest 
      that the formation of tumors within TSC patients may result from aberrantly high 
      levels of mTOR-mediated signaling to downstream targets.
FAU - Tee, Andrew R
AU  - Tee AR
AD  - Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
FAU - Fingar, Diane C
AU  - Fingar DC
FAU - Manning, Brendan D
AU  - Manning BD
FAU - Kwiatkowski, David J
AU  - Kwiatkowski DJ
FAU - Cantley, Lewis C
AU  - Cantley LC
FAU - Blenis, John
AU  - Blenis J
LA  - eng
GR  - GM 51405/GM/NIGMS NIH HHS/United States
GR  - R37 GM041890/GM/NIGMS NIH HHS/United States
GR  - R01 GM051405/GM/NIGMS NIH HHS/United States
GR  - GM 56203/GM/NIGMS NIH HHS/United States
GR  - R01 GM041890/GM/NIGMS NIH HHS/United States
GR  - R01 GM056203/GM/NIGMS NIH HHS/United States
GR  - GM 41890/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20020923
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Amino Acids)
RN  - 0 (Carrier Proteins)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (EIF4EBP1 protein, human)
RN  - 0 (Insulin)
RN  - 0 (Phosphoproteins)
RN  - 0 (Proteins)
RN  - 0 (Repressor Proteins)
RN  - 0 (TSC1 protein, human)
RN  - 0 (TSC2 protein, human)
RN  - 0 (Tuberous Sclerosis Complex 1 Protein)
RN  - 0 (Tuberous Sclerosis Complex 2 Protein)
RN  - 0 (Tumor Suppressor Proteins)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
EIN - Proc Natl Acad Sci U S A. 2021 Aug 17;118(33):. PMID: 34373336
MH  - Adaptor Proteins, Signal Transducing
MH  - Amino Acids/metabolism
MH  - Carrier Proteins/antagonists & inhibitors/chemistry/metabolism
MH  - Cell Cycle Proteins
MH  - Cell Line
MH  - Humans
MH  - In Vitro Techniques
MH  - Insulin/pharmacology
MH  - Models, Biological
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Phosphoproteins/antagonists & inhibitors/chemistry/metabolism
MH  - Phosphorylation
MH  - Point Mutation
MH  - Protein Kinases/genetics/*metabolism
MH  - Proteins/genetics/*metabolism
MH  - Repressor Proteins/genetics/*metabolism
MH  - Ribosomal Protein S6 Kinases/antagonists & inhibitors/metabolism
MH  - Signal Transduction
MH  - TOR Serine-Threonine Kinases
MH  - Tuberous Sclerosis/genetics/metabolism
MH  - Tuberous Sclerosis Complex 1 Protein
MH  - Tuberous Sclerosis Complex 2 Protein
MH  - Tumor Suppressor Proteins
PMC - PMC129715
EDAT- 2002/09/25 06:00
MHDA- 2002/12/05 04:00
PMCR- 2003/04/15
CRDT- 2002/09/25 06:00
PHST- 2002/09/25 06:00 [pubmed]
PHST- 2002/12/05 04:00 [medline]
PHST- 2002/09/25 06:00 [entrez]
PHST- 2003/04/15 00:00 [pmc-release]
AID - 202476899 [pii]
AID - 4768 [pii]
AID - 10.1073/pnas.202476899 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13571-6. doi: 
      10.1073/pnas.202476899. Epub 2002 Sep 23.