PMID- 15805275
OWN - NLM
STAT- MEDLINE
DCOM- 20050526
LR  - 20231120
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 65
IP  - 7
DP  - 2005 Apr 1
TI  - Proteomic analysis reveals hyperactivation of the mammalian target of rapamycin 
      pathway in neurofibromatosis 1-associated human and mouse brain tumors.
PG  - 2755-60
AB  - Individuals with the tumor predisposition syndrome, neurofibromatosis 1 (NF1), 
      are prone to development of nervous system tumors, including neurofibromas and 
      pilocytic astrocytomas. Based on the ability of the NF1 gene product 
      (neurofibromin) to function as a GTPase activating protein for RAS, initial 
      biologically based therapies for NF1-associated tumors focused on the use of RAS 
      inhibitors, but with limited clinical success. In an effort to identify 
      additional targets for therapeutic drug design in NF1, we used an unbiased 
      proteomic approach to uncover unanticipated intracellular signaling pathways 
      dysregulated in Nf1-deficient astrocytes. We found that the expression of 
      proteins involved in promoting ribosome biogenesis was increased in the absence 
      of neurofibromin. In addition, Nf1-deficient astrocytes exhibit high levels of 
      mammalian target of rapamycin (mTOR) pathway activation, which was inhibited by 
      blocking K-RAS or phosphatidylinositol 3-kinase activation. This mTOR pathway 
      hyperactivation was reflected by high levels of ribosomal S6 activation in both 
      Nf1 mutant mouse optic nerve gliomas and in human NF1-associated pilocytic 
      astrocytoma tumors. Moreover, inhibition of mTOR signaling in Nf1-/- astrocytes 
      abrogated their growth advantage in culture, restoring normal proliferative 
      rates. These results suggest that mTOR pathway inhibition may represent a logical 
      and tractable biologically based therapy for brain tumors in NF1.
FAU - Dasgupta, Biplab
AU  - Dasgupta B
AD  - Department of Neurology, Washington University School of Medicine, St. Louis, 
      Missouri, USA.
FAU - Yi, Yijun
AU  - Yi Y
FAU - Chen, David Y
AU  - Chen DY
FAU - Weber, Jason D
AU  - Weber JD
FAU - Gutmann, David H
AU  - Gutmann DH
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Neurofibromin 1)
RN  - 0 (RNA, Messenger)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 90-kDa)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Astrocytes/enzymology/metabolism
MH  - Brain Neoplasms/genetics/*metabolism
MH  - Genes, Neurofibromatosis 1/physiology
MH  - Glioma/genetics/metabolism
MH  - Humans
MH  - Mice
MH  - Mice, Transgenic
MH  - Neurofibromatosis 1/genetics/*metabolism
MH  - Neurofibromin 1/*deficiency/genetics/metabolism
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Protein Kinases/*metabolism
MH  - Proteomics
MH  - RNA, Messenger/genetics/metabolism
MH  - Ribosomal Protein S6 Kinases, 90-kDa/metabolism
MH  - Signal Transduction
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases
EDAT- 2005/04/05 09:00
MHDA- 2005/05/27 09:00
CRDT- 2005/04/05 09:00
PHST- 2005/04/05 09:00 [pubmed]
PHST- 2005/05/27 09:00 [medline]
PHST- 2005/04/05 09:00 [entrez]
AID - 65/7/2755 [pii]
AID - 10.1158/0008-5472.CAN-04-4058 [doi]
PST - ppublish
SO  - Cancer Res. 2005 Apr 1;65(7):2755-60. doi: 10.1158/0008-5472.CAN-04-4058.