PMID- 24318359
OWN - NLM
STAT- MEDLINE
DCOM- 20141204
LR  - 20220317
IS  - 1949-2553 (Electronic)
IS  - 1949-2553 (Linking)
VI  - 5
IP  - 1
DP  - 2014 Jan 15
TI  - A TRAF2 binding independent region of TNFR2 is responsible for TRAF2 depletion 
      and enhancement of cytotoxicity driven by TNFR1.
PG  - 224-36
AB  - Tumor Necrosis Factor (TNF) interacts with two receptors known as TNFR1 and 
      TNFR2. TNFR1 activation may result in either cell proliferation or cell death. 
      TNFR2 activates Nuclear Factor-kappaB (NF-kB) and c-Jun N-terminal kinase (JNK) 
      which lead to transcriptional activation of genes related to cell proliferation 
      and survival. This depends on the binding of TNF Receptor Associated Factor 2 
      (TRAF2) to the receptor. TNFR2 also induces TRAF2 degradation. In this work we 
      have investigated the structural features of TNFR2 responsible for inducing TRAF2 
      degradation and have studied the biological consequences of this activity. We 
      show that when TNFR1 and TNFR2 are co-expressed, TRAF2 depletion leads to an 
      enhanced TNFR1 cytotoxicity which correlates with the inhibition of NF-kB. NF-kB 
      activation and TRAF2 degradation depend of different regions of the receptor 
      since TNFR2 mutants at amino acids 343-349 fail to induce TRAF2 degradation and 
      have lost their ability to enhance TNFR1-mediated cell death but are still able 
      to activate NF-kB. Moreover, whereas NF-kB activation requires TRAF2 binding to 
      the receptor, TRAF2 degradation appears independent of TRAF2 binding. Thus, TNFR2 
      mutants unable to bind TRAF2 are still able to induce its degradation and to 
      enhance TNFR1-mediated cytotoxicity. To test further this receptor crosstalk we 
      have developed a system stably expressing in cells carrying only endogenous TNFR1 
      the chimeric receptor RANK-TNFR2, formed by the extracellular region of RANK 
      (Receptor activator of NF-kB) and the intracellular region of TNFR2.This has made 
      possible to study independently the signals triggered by TNFR1 and TNFR2. In 
      these cells TNFR1 is selectively activated by soluble TNF (sTNF) while RANK-TNFR2 
      is selectively activated by RANKL. Treatment of these cells with sTNF and RANKL 
      leads to an enhanced cytotoxicity.
FAU - Cabal-Hierro, Lucia
AU  - Cabal-Hierro L
AD  - Departamento de Bioquimica y Biologia Molecular and Instituto Universitario de 
      Oncologia del Principado de Asturias (IUOPA), Universidad de Oviedo, Oviedo, 
      Spain.
FAU - Artime, Noelia
AU  - Artime N
FAU - Iglesias, Julian
AU  - Iglesias J
FAU - Prado, Miguel A
AU  - Prado MA
FAU - Ugarte-Gil, Lorea
AU  - Ugarte-Gil L
FAU - Casado, Pedro
AU  - Casado P
FAU - Fernandez-Garcia, Belen
AU  - Fernandez-Garcia B
FAU - Darnay, Bryant G
AU  - Darnay BG
FAU - Lazo, Pedro S
AU  - Lazo PS
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Oncotarget
JT  - Oncotarget
JID - 101532965
RN  - 0 (Receptors, Tumor Necrosis Factor, Type I)
RN  - 0 (Receptors, Tumor Necrosis Factor, Type II)
RN  - 0 (TNF Receptor-Associated Factor 2)
SB  - IM
MH  - Animals
MH  - Apoptosis/physiology
MH  - Cell Growth Processes/physiology
MH  - Cell Line
MH  - Fibroblasts
MH  - HEK293 Cells
MH  - Humans
MH  - Mice
MH  - Receptors, Tumor Necrosis Factor, Type I/*metabolism
MH  - Receptors, Tumor Necrosis Factor, Type II/*metabolism
MH  - Signal Transduction
MH  - TNF Receptor-Associated Factor 2/*metabolism
MH  - Transfection
PMC - PMC3960203
EDAT- 2013/12/10 06:00
MHDA- 2014/12/15 06:00
PMCR- 2014/01/01
CRDT- 2013/12/10 06:00
PHST- 2013/12/10 06:00 [entrez]
PHST- 2013/12/10 06:00 [pubmed]
PHST- 2014/12/15 06:00 [medline]
PHST- 2014/01/01 00:00 [pmc-release]
AID - 1492 [pii]
AID - 10.18632/oncotarget.1492 [doi]
PST - ppublish
SO  - Oncotarget. 2014 Jan 15;5(1):224-36. doi: 10.18632/oncotarget.1492.