PMID- 9813034
OWN - NLM
STAT- MEDLINE
DCOM- 19981221
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 273
IP  - 47
DP  - 1998 Nov 20
TI  - Nuclear factor kB-independent cytoprotective pathways originating at tumor 
      necrosis factor receptor-associated factor 2.
PG  - 31262-72
AB  - Most normal and neoplastic cell types are resistant to tumor necrosis factor 
      (TNF) cytotoxicity unless cotreated with protein or RNA synthesis inhibitors, 
      such as cycloheximide and actinomycin D. Cellular resistance to TNF requires TNF 
      receptor-associated factor 2 (TRAF2), which has been hypothesized to act mainly 
      by mediating activation of the transcription factors nuclear factor kB (NFkB) and 
      activator protein 1 (AP1). NFkB was proposed to switch on transcription of yet 
      unidentified anti-apoptotic genes. To test the possible existence of 
      NFkB-independent cytoprotective pathways, we systematically compared selective 
      trans-dominant inhibitors of the NFkB pathway with inhibitors of TRAF2 signaling 
      for their effect on TNF cytotoxicity. Blockade of TRAF2 function(s) by 
      signaling-deficient oligomerization partners or by molecules affecting TRAF2 
      recruitment to the TNF receptor 1 complex completely abrogated the cytoprotective 
      response. Conversely, sensitization to TNF cytotoxicity induced by a selective 
      NFkB blockade affected only a fraction of TNF-treated cells in an apparently 
      stochastic manner. No cytoprotective role for c-Jun amino-terminal 
      kinases/stress-activated protein kinases (JNKs/SAPKs), which are activated by 
      TRAF2 and contribute to stimulation of activator protein 1 activity, could be 
      demonstrated in the cellular systems tested. Although required for 
      cytoprotection, TRAF2 is not sufficient to protect cells from TNF + cycloheximide 
      cytotoxicity when overexpressed in transfected cells, thus indicating an 
      essential role of additional TNF receptor 1 complex components in the 
      cytoprotective response. Our results indicate that TNF-induced cytoprotection is 
      a complex function requiring the integration of multiple signal transduction 
      pathways.
FAU - Natoli, G
AU  - Natoli G
AD  - Fondazione Andrea Cesalpino, Policlinico Umberto I, University of Rome La 
      Sapienza, Viale del Policlinico 155, 00161 Rome, Italy.
FAU - Costanzo, A
AU  - Costanzo A
FAU - Guido, F
AU  - Guido F
FAU - Moretti, F
AU  - Moretti F
FAU - Bernardo, A
AU  - Bernardo A
FAU - Burgio, V L
AU  - Burgio VL
FAU - Agresti, C
AU  - Agresti C
FAU - Levrero, M
AU  - Levrero M
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (I-kappa B Proteins)
RN  - 0 (NF-kappa B)
RN  - 0 (Nfkbia protein, rat)
RN  - 0 (Protein Synthesis Inhibitors)
RN  - 0 (Proteins)
RN  - 0 (Repressor Proteins)
RN  - 0 (TNF Receptor-Associated Factor 2)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 139874-52-5 (NF-KappaB Inhibitor alpha)
RN  - 98600C0908 (Cycloheximide)
SB  - IM
MH  - Animals
MH  - *Apoptosis
MH  - Cycloheximide/pharmacology
MH  - DNA-Binding Proteins/metabolism
MH  - Dimerization
MH  - *I-kappa B Proteins
MH  - NF-KappaB Inhibitor alpha
MH  - NF-kappa B/antagonists & inhibitors/*metabolism
MH  - Oligodendroglia/drug effects
MH  - Protein Synthesis Inhibitors/pharmacology
MH  - Proteins/antagonists & inhibitors/genetics/*metabolism
MH  - Rats
MH  - Repressor Proteins/metabolism
MH  - Signal Transduction
MH  - TNF Receptor-Associated Factor 2
MH  - Tumor Necrosis Factor-alpha/*pharmacology
MH  - Zinc Fingers
EDAT- 1998/11/13 00:00
MHDA- 1998/11/13 00:01
CRDT- 1998/11/13 00:00
PHST- 1998/11/13 00:00 [pubmed]
PHST- 1998/11/13 00:01 [medline]
PHST- 1998/11/13 00:00 [entrez]
AID - S0021-9258(19)59152-9 [pii]
AID - 10.1074/jbc.273.47.31262 [doi]
PST - ppublish
SO  - J Biol Chem. 1998 Nov 20;273(47):31262-72. doi: 10.1074/jbc.273.47.31262.