PMID- 18490760
OWN - NLM
STAT- MEDLINE
DCOM- 20080718
LR  - 20211203
IS  - 0022-1767 (Print)
IS  - 0022-1767 (Linking)
VI  - 180
IP  - 11
DP  - 2008 Jun 1
TI  - Differential involvement of IkappaB kinases alpha and beta in cytokine- and 
      insulin-induced mammalian target of rapamycin activation determined by Akt.
PG  - 7582-9
AB  - The mammalian target of rapamycin (mTOR) is a mediator of cell growth, survival, 
      and energy metabolism at least partly through its ability to regulate mRNA 
      translation. mTOR is activated downstream of growth factors such as insulin, 
      cytokines such as TNF, and Akt-dependent signaling associated with oncoprotein 
      expression. mTOR is negatively controlled by the tuberous sclerosis complex 1/2 
      (TSC1/2), and activation of Akt induces phosphorylation of TSC2, which blocks the 
      repressive TSC1/2 activity. Previously, we showed that activation of mTOR in 
      PTEN-deficient cancer cells involves IkappaB kinase (IKK) alpha, a catalytic 
      subunit of the IKK complex that controls NF-kappaB activation. Recently, a 
      distinct IKK subunit, IKKbeta, was shown to phosphorylate TSC1 to promote mTOR 
      activation in an Akt-independent manner in certain cells stimulated with TNF and 
      in some cancer cells. In this study, we have explored the involvement of both 
      IKKalpha and IKKbeta in insulin- and TNF-induced mTOR activation. Insulin 
      activation of mTOR requires Akt in a manner that involves IKKalpha, 
      preferentially to IKKbeta, and TSC2 phosphorylation. TNF, in most cells examined, 
      activates Akt to use IKKalpha to control mTOR activation. In MCF7 cells, TNF does 
      not activate Akt and requires IKKbeta to activate mTOR. The results show that 
      Akt-dependent signaling, induced by cytokines or insulin, alters the IKK 
      subunit-dependent control of mTOR.
FAU - Dan, Han C
AU  - Dan HC
AD  - Lineberger Comprehensive Cancer Center, University of North Carolina School of 
      Medicine, Chapel Hill, NC 27599, USA.
FAU - Baldwin, Albert S
AU  - Baldwin AS
LA  - eng
GR  - AI35098/AI/NIAID NIH HHS/United States
GR  - CA75080/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PL  - United States
TA  - J Immunol
JT  - Journal of immunology (Baltimore, Md. : 1950)
JID - 2985117R
RN  - 0 (Chromones)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Insulin)
RN  - 0 (Morpholines)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one)
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 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.10 (CHUK protein, human)
RN  - EC 2.7.11.10 (I-kappa B Kinase)
RN  - EC 2.7.11.10 (IKBKB protein, human)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Cell Line
MH  - Chromones/pharmacology
MH  - Enzyme Inhibitors/pharmacology
MH  - Humans
MH  - I-kappa B Kinase/*metabolism
MH  - Insulin/*metabolism
MH  - Mice
MH  - Mice, Mutant Strains
MH  - Morpholines/pharmacology
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Phosphorylation
MH  - Protein Kinases/*metabolism
MH  - Proto-Oncogene Proteins c-akt/*metabolism
MH  - Sirolimus/metabolism
MH  - TOR Serine-Threonine Kinases
MH  - Tumor Necrosis Factor-alpha/*metabolism
EDAT- 2008/05/21 09:00
MHDA- 2008/07/19 09:00
CRDT- 2008/05/21 09:00
PHST- 2008/05/21 09:00 [pubmed]
PHST- 2008/07/19 09:00 [medline]
PHST- 2008/05/21 09:00 [entrez]
AID - 180/11/7582 [pii]
AID - 10.4049/jimmunol.180.11.7582 [doi]
PST - ppublish
SO  - J Immunol. 2008 Jun 1;180(11):7582-9. doi: 10.4049/jimmunol.180.11.7582.