PMID- 21818401
OWN - NLM
STAT- MEDLINE
DCOM- 20111206
LR  - 20240317
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 6
IP  - 7
DP  - 2011
TI  - Proteomic analysis shows synthetic oleanane triterpenoid binds to mTOR.
PG  - e22862
LID - 10.1371/journal.pone.0022862 [doi]
LID - e22862
AB  - New multifunctional drugs that target multiple disease-relevant networks offer a 
      novel approach to the prevention and treatment of many diseases. New synthetic 
      oleanane triterpenoids (SO), such as CDDO 
      (2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid) and its derivatives, are 
      multifunctional compounds originally developed for the prevention and treatment 
      of inflammation and oxidative stress. However, the protein binding partners and 
      mechanisms of action of these SO are not yet fully understood. Here we 
      characterize the putative target profile of one SO, CDDO-Imidazolide (CDDO-Im), 
      by combining affinity purification with mass spectroscopic proteomic analysis to 
      identify 577 candidate binding proteins in whole cells. This SO 
      pharmaco-interactome consists of a diverse but interconnected set of signaling 
      networks; bioinformatic analysis of the protein interactome identified canonical 
      signaling pathways targeted by the SO, including retinoic acid receptor (RAR), 
      estrogen receptor (ER), insulin receptor (IR), janus kinase/signal transducers 
      and activators of transcription (JAK/STAT), and phosphatase and tensin homolog 
      (PTEN). Pull-down studies then further validated a subset of the putative 
      targets. In addition, we now show for the first time that the mammalian target of 
      rapamycin (mTOR) is a direct target of CDDO-Im. We also show that CDDO-Im blocks 
      insulin-induced activation of this pathway by binding to mTOR and inhibiting its 
      kinase activity. Our basic studies confirm that the SO, CDDO-Im, acts on a 
      protein network to elicit its pharmacological activity.
FAU - Yore, Mark M
AU  - Yore MM
AD  - Department of Pharmacology, Dartmouth Medical School, Hanover, New Hampshire, 
      United States of America.
FAU - Kettenbach, Arminja N
AU  - Kettenbach AN
FAU - Sporn, Michael B
AU  - Sporn MB
FAU - Gerber, Scott A
AU  - Gerber SA
FAU - Liby, Karen T
AU  - Liby KT
LA  - eng
GR  - P30 CA023108/CA/NCI NIH HHS/United States
GR  - R01 CA078814/CA/NCI NIH HHS/United States
GR  - R01 CA78814/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20110727
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole)
RN  - 0 (Imidazoles)
RN  - 6SMK8R7TGJ (Oleanolic Acid)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Biotinylation
MH  - Chromatography, Liquid
MH  - Computational Biology
MH  - HEK293 Cells
MH  - Humans
MH  - Imidazoles/chemistry/metabolism
MH  - Mass Spectrometry
MH  - Oleanolic Acid/analogs & derivatives/chemistry/*metabolism
MH  - Protein Binding
MH  - Proteomics/*methods
MH  - Reproducibility of Results
MH  - TOR Serine-Threonine Kinases/*metabolism
PMC - PMC3144948
COIS- Competing Interests: Karen Liby and Michael Sporn are inventors on patents 
      dealing with chemical synthesis of new triterpenoids and their application in 
      treatment of cancer, as well as in inflammatory diseases, including human kidney 
      disease (patent 6,974,801 issued 1/1/2004). They strongly adhere to the PLoS ONE 
      policy on sharing of data and materials. The Sporn Laboratory has a long history 
      of being extremely free in sharing of materials, with no strings attached, with 
      other laboratories throughout the world.
EDAT- 2011/08/06 06:00
MHDA- 2011/12/13 00:00
PMCR- 2011/07/27
CRDT- 2011/08/06 06:00
PHST- 2011/04/18 00:00 [received]
PHST- 2011/06/30 00:00 [accepted]
PHST- 2011/08/06 06:00 [entrez]
PHST- 2011/08/06 06:00 [pubmed]
PHST- 2011/12/13 00:00 [medline]
PHST- 2011/07/27 00:00 [pmc-release]
AID - PONE-D-11-06910 [pii]
AID - 10.1371/journal.pone.0022862 [doi]
PST - ppublish
SO  - PLoS One. 2011;6(7):e22862. doi: 10.1371/journal.pone.0022862. Epub 2011 Jul 27.