PMID- 10640750
OWN - NLM
STAT- MEDLINE
DCOM- 20000224
LR  - 20220330
IS  - 0022-1767 (Print)
IS  - 0022-1767 (Linking)
VI  - 164
IP  - 3
DP  - 2000 Feb 1
TI  - Phosphatidylinositol 3-kinase as a mediator of TNF-induced NF-kappa B activation.
PG  - 1355-63
AB  - The activation of transcription factor NF-kappa B by TNF involves the stimulation 
      of a novel signaling cascade. In this paper we show that phosphatidylinositol 
      3-kinase (PI 3-kinase) may play a pivotal role in TNF-mediated activation of 
      NF-kappa B-dependent genes. Consistent with its involvement in TNF signaling, PI 
      3-kinase activities in HepG2 and U937 cells can be stimulated by TNF in a rapid 
      but transient manner through a mechanism that may involve its association with 
      the insulin receptor substrate-1. A dominant-negative mutant of the p85 
      regulatory subunit of PI 3-kinase, which is a potent inhibitor of PI 3-kinase 
      signaling, effectively blocked the TNF-induced expression of an NF-kappa 
      B-dependent reporter gene. Although PI 3-kinase may be required for NF-kappa B 
      activation, overexpression of its p110 catalytic subunit alone was unable to 
      induce an NF-kappa B/chloramphenicol acetyltransferase (CAT) reporter gene. 
      However, when TNF was added to p110-overexpressing cells, there was a synergistic 
      activation of the NF-kappa B/CAT reporter, suggesting that other TNF-inducible 
      signals may cooperate with PI 3-kinase to activate NF-kappa B. Consistent with 
      its role in NF-kappa B activation, inhibition of PI 3-kinase activity by 
      wortmannin or LY294002 greatly potentiated TNF-induced apoptosis. This 
      TNF/wortmannin-induced apoptosis was markedly prevented in cells overexpressing 
      Rel A. Taken together, our results indicate that a PI 3-kinase-regulated step in 
      TNF-signaling is critical for the expression of NF-kappa B-dependent genes.
FAU - Reddy, S A
AU  - Reddy SA
AD  - Department of Biochemistry, University of Texas, M. D. Anderson Cancer Center, 
      Houston, TX 77030, USA.
FAU - Huang, J H
AU  - Huang JH
FAU - Liao, W S
AU  - Liao WS
LA  - eng
GR  - AR38858/AR/NIAMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Immunol
JT  - Journal of immunology (Baltimore, Md. : 1950)
JID - 2985117R
RN  - 0 (Androstadienes)
RN  - 0 (Chromones)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Morpholines)
RN  - 0 (NF-kappa B)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Retroviridae Proteins, Oncogenic)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one)
RN  - EC 2.3.1.28 (Chloramphenicol O-Acetyltransferase)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.11.1 (Oncogene Protein v-akt)
RN  - XVA4O219QW (Wortmannin)
SB  - IM
MH  - Androstadienes/pharmacology
MH  - Apoptosis/drug effects
MH  - Catalytic Domain/physiology
MH  - Chloramphenicol O-Acetyltransferase/genetics
MH  - Chromones/pharmacology
MH  - DNA-Binding Proteins/metabolism
MH  - Drug Synergism
MH  - Enzyme Activation/genetics
MH  - Gene Expression Regulation
MH  - Genes, Reporter
MH  - Humans
MH  - Morpholines/pharmacology
MH  - NF-kappa B/antagonists & inhibitors/genetics/*metabolism
MH  - Oncogene Protein v-akt
MH  - Phosphatidylinositol 3-Kinases/metabolism/*physiology
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Protein-Tyrosine Kinases/metabolism
MH  - Retroviridae Proteins, Oncogenic/metabolism
MH  - Signal Transduction/genetics
MH  - Tumor Cells, Cultured
MH  - Tumor Necrosis Factor-alpha/*physiology
MH  - U937 Cells
MH  - Wortmannin
EDAT- 2000/01/21 09:00
MHDA- 2000/02/26 09:00
CRDT- 2000/01/21 09:00
PHST- 2000/01/21 09:00 [pubmed]
PHST- 2000/02/26 09:00 [medline]
PHST- 2000/01/21 09:00 [entrez]
AID - ji_v164n3p1355 [pii]
AID - 10.4049/jimmunol.164.3.1355 [doi]
PST - ppublish
SO  - J Immunol. 2000 Feb 1;164(3):1355-63. doi: 10.4049/jimmunol.164.3.1355.