PMID- 14581487
OWN - NLM
STAT- MEDLINE
DCOM- 20040210
LR  - 20211203
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 279
IP  - 2
DP  - 2004 Jan 9
TI  - Inhibition of phosphatidylinositol 3-kinase- and ERK MAPK-regulated protein 
      synthesis reveals the pro-apoptotic properties of CD40 ligation in carcinoma 
      cells.
PG  - 1010-9
AB  - CD40, a member of the tumor necrosis factor receptor superfamily, is frequently 
      expressed in carcinomas where its stimulation results in induction of apoptosis 
      when de novo protein synthesis is inhibited. The requirement of protein synthesis 
      inhibition for efficient killing suggests that CD40 transduces potent survival 
      signals capable of suppressing its pro-apoptotic effects. We have found that 
      inhibition of CD40 signaling on the phosphatidylinositol 3-kinase (PI3K) and ERK 
      MAPK but not on the p38 MAPK axis disrupts this balance and sensitizes carcinoma 
      cells to CD40-mediated cell death. The CD40-mediated PI3K and ERK activities were 
      found to converge on the regulation of protein synthesis in carcinoma cells via a 
      pathway involving the activation of p90 ribosomal S6 kinase (p90Rsk) and p70S6 
      kinases, upstream of the translation elongation factor eEF2. In addition, CD40 
      ligation was found to mediate a PI3K- and mammalian target of rapamycin 
      (mTOR)-dependent phosphorylation of 4E-BP1 and its subsequent dissociation from 
      the mRNA cap-binding protein eIF4E as well as an ERK-dependent phosphorylation of 
      eIF4E, thus promoting translation initiation. Concomitantly, the antiapoptotic 
      protein cFLIP was found to be induced in CD40 ligand-stimulated carcinoma cells 
      in a PI3K-, ERK-, and mammalian target of rapamycin (mTOR)-dependent manner and 
      down-regulation of cFLIPS expression sensitized to CD40-mediated carcinoma cell 
      death. These data underline the significance of the PI3K and ERK pathways in 
      controlling the balance between CD40-mediated survival and death signals through 
      the regulation of the protein synthesis machinery. Pharmacological agents that 
      target this machinery or its upstream kinases could, therefore, be exploited for 
      CD40-based tumor therapy.
FAU - Davies, Clare C
AU  - Davies CC
AD  - Cancer Research United Kingdom Institute for Cancer Studies, The University of 
      Birmingham Medical School, Birmingham B15 2TA, United Kingdom.
FAU - Mason, Joanne
AU  - Mason J
FAU - Wakelam, Michael J O
AU  - Wakelam MJ
FAU - Young, Lawrence S
AU  - Young LS
FAU - Eliopoulos, Aristides G
AU  - Eliopoulos AG
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20031027
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (CASP8 and FADD-Like Apoptosis Regulating Protein)
RN  - 0 (CD40 Antigens)
RN  - 0 (CFLAR protein, human)
RN  - 0 (Carrier Proteins)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (Culture Media, Serum-Free)
RN  - 0 (EIF4EBP1 protein, human)
RN  - 0 (Eukaryotic Initiation Factor-4E)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Phosphoproteins)
RN  - 147205-72-9 (CD40 Ligand)
RN  - 86-01-1 (Guanosine Triphosphate)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.- (MKNK1 protein, human)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 90-kDa)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing
MH  - Apoptosis
MH  - CASP8 and FADD-Like Apoptosis Regulating Protein
MH  - CD40 Antigens/biosynthesis/*metabolism
MH  - CD40 Ligand/metabolism
MH  - Carrier Proteins/metabolism
MH  - Cell Cycle Proteins
MH  - Cell Line
MH  - Cell Line, Tumor
MH  - Culture Media, Serum-Free/pharmacology
MH  - Down-Regulation
MH  - Eukaryotic Initiation Factor-4E/metabolism
MH  - Guanosine Triphosphate/metabolism
MH  - HeLa Cells
MH  - Humans
MH  - *Intracellular Signaling Peptides and Proteins
MH  - *MAP Kinase Signaling System
MH  - Mitogen-Activated Protein Kinases/*metabolism
MH  - Models, Biological
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Phosphoproteins/metabolism
MH  - Phosphorylation
MH  - Protein Kinases/metabolism
MH  - Protein Serine-Threonine Kinases/metabolism
MH  - Ribosomal Protein S6 Kinases, 70-kDa/metabolism
MH  - Ribosomal Protein S6 Kinases, 90-kDa/metabolism
MH  - TOR Serine-Threonine Kinases
MH  - Time Factors
MH  - p38 Mitogen-Activated Protein Kinases
EDAT- 2003/10/29 05:00
MHDA- 2004/02/11 05:00
CRDT- 2003/10/29 05:00
PHST- 2003/10/29 05:00 [pubmed]
PHST- 2004/02/11 05:00 [medline]
PHST- 2003/10/29 05:00 [entrez]
AID - S0021-9258(18)52710-1 [pii]
AID - 10.1074/jbc.M303820200 [doi]
PST - ppublish
SO  - J Biol Chem. 2004 Jan 9;279(2):1010-9. doi: 10.1074/jbc.M303820200. Epub 2003 Oct 
      27.