PMID- 12403809
OWN - NLM
STAT- MEDLINE
DCOM- 20021122
LR  - 20211203
IS  - 0021-9525 (Print)
IS  - 1540-8140 (Electronic)
IS  - 0021-9525 (Linking)
VI  - 159
IP  - 2
DP  - 2002 Oct 28
TI  - Tuberous sclerosis complex tumor suppressor-mediated S6 kinase inhibition by 
      phosphatidylinositide-3-OH kinase is mTOR independent.
PG  - 217-24
AB  - The evolution of mitogenic pathways has led to the parallel requirement for 
      negative control mechanisms, which prevent aberrant growth and the development of 
      cancer. Principally, such negative control mechanisms are represented by tumor 
      suppressor genes, which normally act to constrain cell proliferation (Macleod, K. 
      2000. Curr. Opin. Genet. Dev. 10:81-93). Tuberous sclerosis complex (TSC) is an 
      autosomal-dominant genetic disorder, characterized by mutations in either TSC1 or 
      TSC2, whose gene products hamartin (TSC1) and tuberin (TSC2) constitute a 
      putative tumor suppressor complex (TSC1-2; van Slegtenhorst, M., M. Nellist, B. 
      Nagelkerken, J. Cheadle, R. Snell, A. van den Ouweland, A. Reuser, J. Sampson, D. 
      Halley, and P. van der Sluijs. 1998. Hum. Mol. Genet. 7:1053-1057). Little is 
      known with regard to the oncogenic target of TSC1-2, however recent genetic 
      studies in Drosophila have shown that S6 kinase (S6K) is epistatically dominant 
      to TSC1-2 (Tapon, N., N. Ito, B.J. Dickson, J.E. Treisman, and I.K. Hariharan. 
      2001. Cell. 105:345-355; Potter, C.J., H. Huang, and T. Xu. 2001. Cell. 
      105:357-368). Here we show that loss of TSC2 function in mammalian cells leads to 
      constitutive S6K1 activation, whereas ectopic expression of TSC1-2 blocks this 
      response. Although activation of wild-type S6K1 and cell proliferation in 
      TSC2-deficient cells is dependent on the mammalian target of rapamycin (mTOR), by 
      using an S6K1 variant (GST-DeltaC-S6K1), which is uncoupled from mTOR signaling, 
      we demonstrate that TSC1-2 does not inhibit S6K1 via mTOR. Instead, we show by 
      using wortmannin and dominant interfering alleles of phosphatidylinositide-3-OH 
      kinase (PI3K) that increased S6K1 activation is contingent upon the suppression 
      of TSC2 function by PI3K in normal cells and is PI3K independent in 
      TSC2-deficient cells.
FAU - Jaeschke, Anja
AU  - Jaeschke A
AD  - Cancer Research UK Centre for Cell and Molecular Biology, Institute for Cancer 
      Research, 237 Fulham Road, London SW3 6JB, UK.
FAU - Hartkamp, Joerg
AU  - Hartkamp J
FAU - Saitoh, Masao
AU  - Saitoh M
FAU - Roworth, Wendy
AU  - Roworth W
FAU - Nobukuni, Takahiro
AU  - Nobukuni T
FAU - Hodges, Angela
AU  - Hodges A
FAU - Sampson, Julian
AU  - Sampson J
FAU - Thomas, George
AU  - Thomas G
FAU - Lamb, Richard
AU  - Lamb R
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20021028
PL  - United States
TA  - J Cell Biol
JT  - The Journal of cell biology
JID - 0375356
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Carrier Proteins)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (Eif4ebp1 protein, mouse)
RN  - 0 (Eukaryotic Initiation Factors)
RN  - 0 (Phosphoproteins)
RN  - 0 (Proteins)
RN  - 0 (Recombinant Proteins)
RN  - 0 (Repressor Proteins)
RN  - 0 (Tsc1 protein, mouse)
RN  - 0 (Tsc2 protein, mouse)
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, mouse)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing
MH  - Animals
MH  - COS Cells
MH  - Carrier Proteins/metabolism
MH  - Cell Cycle Proteins
MH  - Eukaryotic Initiation Factors
MH  - Fibroblasts/cytology/enzymology
MH  - Genes, Tumor Suppressor/physiology
MH  - Mice
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Phosphoproteins/metabolism
MH  - Phosphorylation
MH  - Protein Biosynthesis/physiology
MH  - Protein Kinases/*metabolism
MH  - Proteins/metabolism
MH  - Recombinant Proteins/metabolism
MH  - Repressor Proteins/*metabolism
MH  - Ribosomal Protein S6 Kinases/*metabolism
MH  - Signal Transduction/physiology
MH  - TOR Serine-Threonine Kinases
MH  - Transfection
MH  - Tuberous Sclerosis/*metabolism
MH  - Tuberous Sclerosis Complex 1 Protein
MH  - Tuberous Sclerosis Complex 2 Protein
MH  - Tumor Suppressor Proteins
PMC - PMC2173059
EDAT- 2002/10/31 04:00
MHDA- 2002/11/26 04:00
PMCR- 2003/04/28
CRDT- 2002/10/31 04:00
PHST- 2002/10/31 04:00 [pubmed]
PHST- 2002/11/26 04:00 [medline]
PHST- 2002/10/31 04:00 [entrez]
PHST- 2003/04/28 00:00 [pmc-release]
AID - jcb.jcb.200206108 [pii]
AID - 200206108 [pii]
AID - 10.1083/jcb.jcb.200206108 [doi]
PST - ppublish
SO  - J Cell Biol. 2002 Oct 28;159(2):217-24. doi: 10.1083/jcb.jcb.200206108. Epub 2002 
      Oct 28.